bluuebunny/crossref_metadata_2025 huggingface dataset:
Current status of reimbursement practices for remote monitoring of cardiac implantable electrical devices across Europe
Authors: Boriani Giuseppe , Burri Haran , Svennberg Emma , Imberti Jacopo Francesco , Merino Josè Luis , Leclercq Christophe
Published: July 2022

Remote monitoring (RM) of cardiac implantable electrical devices (CIEDs) is currently proposed as a standard of care for CIEDs follow-up, as recommended by major cardiology societies worldwide. By detecting a series of relevant device and patient-related parameters, RM is a valuable option for early detection of CIEDs' technical issues, as well as changes in parameters related to cardio-respiratory functions. Moreover, RM may allow longer spacing between in-office follow-ups and better organization of in-hospital resources. Despite these potential advantages, resulting in improved patient safety, we are still far from a widespread diffusion of RM across Europe. Reimbursement policies across Europe still show an important heterogeneity and have been considered as an important barrier to full implementation of RM as a standard for the follow-up of all the patients with pacemakers, defibrillators, devices for cardiac resynchronization, or implantable loop recorders. Indeed, in many countries, there are still inertia and unresponsiveness to the request for widespread implementation of RM for CIEDs, although an improvement was found in some countries as compared to years ago, related to the provision of some form of reimbursement. As a matter of fact, the COVID-19 pandemic has promoted an increased use of digital health for connecting physicians to patients, even if digital literacy may be a limit for the widespread implementation of telemedicine. CIEDs have the advantage of making possible RM with an already defined organization and reliable systems for data transmissions that can be easily implemented as a standard of care for present and future cardiology practice.
Models for the evolution of seamounts
Authors: Wessel Paul , Watts Anthony B , Kim Seung-Sep , Sandwell David T
Published: July 2022

Seamounts are volcanic constructs that litter the seafloor. They are important for understanding numerous aspects of marine science, such as plate tectonics, the volcanic melt budget, oceanic circulation, tsunami wave diffraction, tidal energy dissipation and mass wasting. Geometrically, seamounts come in many sizes and shapes, and for the purpose of modelling them for morphological, gravimetric or isostatic studies it is convenient to have simple analytical models whose properties are well known. Here, we present a family of seamount models that may be used in such studies, covering both the initial construction phase and later mass-wasting by sectoral collapses. We also derive realistic axisymmetric density variations that are compatible with observed first-order structure from seismic tomography studies.
A multitask encoder–decoder to separate earthquake and ambient noise signal in seismograms
Authors: Yin Jiuxun , Denolle Marine A , He Bing
Published: July 2022

Seismograms contain multiple sources of seismic waves, from distinct transient signals such as earthquakes to continuous ambient seismic vibrations such as microseism. Ambient vibrations contaminate the earthquake signals, while the earthquake signals pollute the ambient noise’s statistical properties necessary for ambient-noise seismology analysis. Separating ambient noise from earthquake signals would thus benefit multiple seismological analyses. This work develops a multitask encoder–decoder network named WaveDecompNet to separate transient signals from ambient signals directly in the time domain for 3-component seismograms. We choose the active-volcanic Big Island in Hawai’i as a natural laboratory given its richness in transients (tectonic and volcanic earthquakes) and diffuse ambient noise (strong microseism). The approach takes a noisy 3-component seismogram as input and independently predicts the 3-component earthquake and noise waveforms. The model is trained on earthquake and noise waveforms from the STandford EArthquake Dataset (STEAD) and on the local noise of seismic station IU.POHA. We estimate the network’s performance by using the explained variance metric on both earthquake and noise waveforms. We explore different neural network designs for WaveDecompNet and find that the model with long-short-term memory (LSTM) performs best over other structures. Overall, we find that WaveDecompNet provides satisfactory performance down to a signal-to-noise ratio (SNR) of 0.1. The potential of the method is (1) to improve broad-band SNR of transient (earthquake) waveforms and (2) to improve local ambient noise to monitor the Earth’s structure using ambient noise signals. To test this, we apply a short-time average to a long-time average filter and improve the number of detected events. We also measure single-station cross-correlation functions of the recovered ambient noise and establish their improved coherence through time and over different frequency bands. We conclude that WaveDecompNet is a promising tool for a broad range of seismological research.
Non-cell-autonomous activation of hedgehog signaling contributes to disease progression in a mouse model of renal cystic ciliopathy
Authors: Hsieh Chia-Ling , Jerman Stephanie Justine , Sun Zhaoxia
Published: July 2022

Polycystic kidney disease (PKD) is a ciliopathy characterized by fluid-filled epithelial cysts in the kidney. Although it is well established that the primary cilium is essential for hedgehog (HH) signaling and HH signaling is abnormally activated in multiple PKD models, the mechanism and function of HH activation in PKD pathogenesis remain incompletely understood. Here we used a transgenic HH reporter mouse line to identify the target tissue of HH signaling in Arl13f/f;Ksp-Cre mutant kidney, in which the cilia biogenesis gene Arl13b is specifically deleted in epithelial cells of the distal nephron. In addition, we used a co-culture system to dissect cross-talk between epithelial and mesenchymal cells in the absence of expanding cysts. Finally, we treated Arl13bf/f;Ksp-Cre mice with the GLI inhibitor GANT61 and analyzed its impact on PKD progression in this model. We found that deletion of Arl13b in epithelial cells in the mouse kidney, in vivo, led to non-cell-autonomous activation of the HH pathway in the interstitium. In vitro, when co-cultured with mesenchymal cells, Arl13b−/− epithelial cells produced more sonic hedgehog in comparison to cells expressing Arl13b. Reciprocally, HH signaling was activated in mesenchymal cells co-cultured with Arl13b−/− epithelial cells. Finally, whole body inhibition of the HH pathway by GANT61 reduced the number of proliferating cells, inhibited cyst progression and fibrosis and preserved kidney function in Arl13bf/f;Ksp-Cre mice. Our results reveal non-cell-autonomous activation of HH signaling in the interstitium of the Arl13bf/f;Ksp-Cre kidney and suggest that abnormal activation of the HH pathway contributes to disease progression.
The Impacts of Transdermal Application of Corticosterone on Toad (Rhinella icterica) Immunity
Authors: Assis Vania Regina , Titon Stefanny Christie Monteiro , Titon Jr. Braz , Gomes Fernando Ribeiro
Published: July 2022

Recent studies have shown that acute physiological increases in endogenous glucocorticoid levels have immunostimulatory effects. Although post-acute stress immunosuppressive effects have also been described, the difference between enhancing and suppressing the immune response seems mediated by the stressor's duration, intensity, and the immune component under analysis. To elicit physiologically relevant corticosterone levels that can be found in Rhinella icterica toads after stressful events (e.g., restraint or captivity) and understand how acute increased glucocorticoid levels of different intensities affect corticosterone and testosterone plasma levels and immune parameters (in vitro plasma bacterial killing ability, neutrophil-to-lymphocyte ratio, and in vivo phagocytosis of peritoneal leukocytes), we submitted toads to the transdermal application of two corticosterone doses (1 and 10 μg). Corticosterone transdermal application increased corticosterone plasma levels with different intensities: 3 times for 1 μg and fourteen times for 10 μg, compared to the vehicle, and the neutrophil-to-lymphocyte ratio increased regardless of the corticosterone dose. However, there was no effect on testosterone levels and bacterial killing ability. Interestingly, both corticosterone doses promoted immunosuppression, decreasing peritoneal leukocytes' phagocytosis activity by 60% for toads receiving the dose of 1µg and 40% for those receiving 10 μg. Our results show the complexity of the relationship between increased corticosterone levels and immunomodulation. The different corticosterone doses promoted increases of distinct magnitudes in corticosterone plasma levels, with the less intense increase in corticosterone levels generating greater cell-mediated immunosuppression. Future studies using different corticosterone doses to achieve and compare physiological vs. pharmacological hormone levels are imperative to understanding these interrelationships between corticosterone and immune response.
Sex Differences in Serotonin 5-HT 1A Receptor Responses to Repeated Restraint Stress in Adult Male and Female Rats
Authors: Philippe Tristan J , Bao Lexia , Koblanski Maya E , Viau Victor
Published: July 2022

Background

Male and female rats were exposed to repeated restraint to determine how changes in serotonin (5-hydroxytryptamine; 5-HT) 1A receptors associate with stress hypothalamic-pituitary-adrenal (HPA) axis habituation.

Methods

In response to 2-hour episodes of restraint, repeated daily for 5 consecutive days, males and females displayed reliable declines in HPA output, indicated by diminished adrenocorticotropin and corticosterone secretory responses. Using the 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) as a pharmacological challenge for inducing hypothermia and elevations in plasma corticosterone, males displayed sensitized hypothermal responses after repeated restraint, whereas corticosterone responses to 8-OH-DPAT were enhanced in both sexes following single or repeated exposure.

Results

Only males showed elevations in 5-HT 1A receptor G-protein coupling responses in the dorsal raphe after repeated restraint, whereas only females showed an increase in 5-HT 1A receptor responses in the hippocampus following single or repeated exposure. G-protein coupling responses within both regions correlated positively with 5-HT 1A receptor binding capacity. Thus, despite expressing similar capacities for stress HPA axis habituation, males and females emerged from repeated restraint to show region-specific changes in 5-HT 1A receptor function that may be explained, at least in part, by changes in receptor availability.

Conclusions

Based on the hypothermal and corticosteroid responses to 8-OH-DPAT, the present data suggest that stress habituation is met by an increase in the sensitivity of presynaptic 5-HT 1A receptors in males and by an increase in the sensitivity of a population of postsynaptic receptors in both sexes.
Efficacy of Omadacycline or Vancomycin Combined With Germinants for PreventingClostridioides difficileRelapse in a Murine Model
Authors: Budi Noah D , Godfrey Jared J , Safdar Nasia , Shukla Sanjay K , Rose Warren E
Published: July 2022

Background

Clostridioides difficile infections (CDI) and recurrence (rCDI) are major health care burdens. Recurrence is likely caused by spores in the gastrointestinal tract that germinate after antibiotic therapy. This murine study explores germinant-antibiotic combinations for CDI.

Methods

Previously described murine models were evaluated using C. difficile VPI 10463. The severe model compared omadacycline versus vancomycin in survival, weight loss, clinical scoring, and C. difficile toxin production. The nonsevere model compared these antibiotics with and without germinants (solution of sodium taurocholate, taurine, sodium docusate, calcium gluconate). Additionally, colon histopathology, bile acid analysis, environmental/spore shedding, and 16S sequencing was evaluated.

Results

In the severe model, omadacycline-treated mice had 60% survival versus 13.3% with vancomycin (hazard ratio [HR], 0.327; 95% confidence interval [CI],.126–.848; P = .015) along with decreased weight loss, and disease severity. In the nonsevere model, all mice survived with antibiotic-germinant treatment versus 60% antibiotics alone (HR, 0.109; 95% CI, .02–.410; P = .001). Omadacycline resulted in less changes in bile acids and microbiota composition. Germinant-treated mice showed no signs of rCDI, spore shedding, or significant toxin production at 15 days.

Conclusions

In murine models of CDI, omadacycline improved survival versus vancomycin. Germinant-antibiotic combinations were more effective at preventing rCDI compared to antibiotics alone without inducing toxin production.
Risk-reducing mastectomy for women with hereditary breast and ovarian cancer (HBOC): analytical results of data from the Japanese Organization of HBOC
Authors: Ohsumi Shozo , Nakamura Seigo , Miyata Hiroaki , Watanabe Chie , Den Hiroki , Arai Masami
Published: July 2022

Background

Risk-reducing mastectomy is one option for women with hereditary breast and ovarian cancer to reduce the risk of breast cancer.

Patients and methods

We analyzed data of the Japanese Organization of Hereditary Breast and Ovarian Cancer on women who were diagnosed as hereditary breast and ovarian cancer by BRCA germline genetic testing between 2010 and 2019 to reveal the rate and likelihood of risk-reducing mastectomy.

Results

There were 412 women with BRCA1, 271 with BRCA2 and 4 with both female pathogenic variants. Ninety (13.1%) received risk-reducing mastectomy. The rates of risk-reducing mastectomy were statistically significantly higher in women with BRCA1 pathogenic variants than BRCA2, in women who had breast cancer than those who did not, in women with a breast cancer family history than in those without, in mothers than in those without children, in women who were receiving surveillance with MRI than those who were not and in women who received risk-reducing salpingo-oophorectomy than in those who did not on univariate analyses. The ages when they received the genetic testing were statistically significantly younger in the women receiving risk-reducing mastectomy than those who did not receive it. The women with BRCA1 pathogenic variants, personal history of breast cancer, mothers, those receiving MRI surveillance and younger women were independently significantly more likely to receive risk-reducing mastectomy based on multivariate analysis.

Conclusions

The rate of risk-reducing mastectomy was not high in Japan; however, risk-reducing surgery was approved by the Japanese National Medical Insurance for hereditary breast and ovarian cancer patients with breast and/or ovarian cancer in 2020, so this rate will increase.
Colour evolution of Betelgeuse and Antares over two millennia, derived from historical records, as a new constraint on mass and age
Authors: Neuhäuser R , Torres G , Mugrauer M , Neuhäuser D L , Chapman J , Luge D , Cosci M
Published: July 2022

After core hydrogen burning, massive stars evolve from blue-white dwarfs to red supergiants by expanding, brightening, and cooling within few millennia. We discuss a previously neglected constraint on mass, age, and evolutionary state of Betelgeuse and Antares, namely their observed colour evolution over historical times: We place all 236 stars bright enough for their colour to be discerned by the unaided eye (V ≤ 3.3 mag) on the colour-magnitude-diagram (CMD), and focus on those in the Hertzsprung gap. We study pre-telescopic records on star colour with historically critical methods to find stars that have evolved noticeably in colour within the last millennia. Our main result is that Betelgeuse was recorded with a colour significantly different (non-red) than today (red, B − V = 1.78 ± 0.05 mag). Hyginus (Rome) and Sima Qian (China) independently report it two millennia ago as appearing like Saturn (B − V = 1.09 ± 0.16 mag) in colour and ‘yellow’ (quantifiable as B − V = 0.95 ± 0.35 mag), respectively (together, 5.1σ different from today). The colour change of Betelgeuse is a new, tight constraint for single-star theoretical evolutionary models (or merger models). It is most likely located less than one millennium past the bottom of the red giant branch, before which rapid colour evolution is expected. Evolutionary tracks from MIST consistent with both its colour evolution and its location on the CMD suggest a mass of ∼14 M⊙ at ∼14 Myr. The (roughly) constant colour of Antares for the last three millennia also constrains its mass and age. Wezen was reported white historically, but is now yellow.
Non-Gaussianity constraints with anisotropic μ distortion measurements from Planck
Authors: Rotti Aditya , Ravenni Andrea , Chluba Jens
Published: July 2022

Primordial non-Gaussianity can source μ-distortion anisotropies that are correlated with the large-scale temperature and polarization signals of the cosmic microwave background (CMB). A measurement of μT and μE correlations can therefore be used to constrain it on wavelengths of perturbations not directly probed by the standard CMB anisotropies. We carry out a first rigorous search for μ-distortion anisotropies with Planck data, applying the well-tested constrained ILC component-separation method combined with the needlet framework. We correlate the reconstructed μ map with the CMB anisotropies to derive constraints on the amplitude fNL of the local form bispectrum, specifically on the squeezed configurations with effective wavenumbers $k_s \simeq {740}\, \mathrm{Mpc^{-1}}$ and $k_L \simeq {0.05}\, \mathrm{Mpc^{-1}}$, improving previously estimated constraints by more than an order of magnitude. This enhancement is owing to the fact that we are able to use the full multipole information by carefully controlling biases and systematic effects in the analysis. We also for the first time incorporate constraints from measurements of μE correlations, which further tighten the limits. A combination of the derived Planck μT and μE power spectra yields |fNL| ≲ 6800 (95 per cent c.l.) on this highly squeezed bispectrum. This is only ≃3 times weaker than the anticipated constraint from Litebird. Furthermore we show that a combination of Litebird with Planck can improve the expected future constraint by ${\simeq}20{{\%}}$. These limits can be used to constrain multifield inflation models and primordial black hole formation scenarios, thus providing a promising novel avenue forward in CMB cosmology.
The N2 production rate in comet C/2016 R2 (PanSTARRS)
Authors: Anderson S E , Rousselot P , Noyelles B , Opitom C , Jehin E , Hutsemékers D , Manfroid J
Published: July 2022

Observations of comet C/2016 R2 (PanSTARRS) have revealed exceptionally bright emission bands of N$_2^+$, the strongest ever observed in a comet spectrum. Alternatively, it appears to be poor in CN compared to other comets, and remarkably depleted in H2O. Here, we quantify the N2 production rate from N$_2^+$ emission lines using the Haser model. We derived effective parent and daughter scale lengths for N2 producing N$_2^+$. This is the first direct measurement of such parameters. Using a revised fluorescence efficiency for N$_2^+$, the resulting production rate of molecular nitrogen is inferred to be Q(N2) ∼ 1 × 1028 molecules s−1 on average for 2018 February 11, 12, and 13, the highest for any known comet. Based on a CO production rate of Q(CO) ∼ 1.1 × 1029 molecules s−1, we find Q(N2)/Q(CO) ∼ 0.09, which is consistent with the N$_2^+$/CO+ ratio derived from the observed intensities of N$_2^+$ and CO+ emission lines. We also measure significant variations in this production rate between our three observing nights, with Q(N2) varying by plus or minus 20 per cent according to the average value.
The VMC survey – XLIX. Discovery of a population of quasars dominated by nuclear dust emission behind the Magellanic Clouds
Authors: Pennock Clara M , van Loon Jacco Th , Anih Joy O , Maitra Chandreyee , Haberl Frank , Sansom Anne E , Ivanov Valentin D , Cowley Michael J , Afonso José , Antón Sonia , Cioni Maria-Rosa L , Craig Jessica E M , Filipović Miroslav D , Hopkins Andrew M , Nanni Ambra , Prandoni Isabella , Vardoulaki Eleni
Published: July 2022

Following the discovery of SAGE0536AGN (z ∼ 0.14), with the strongest 10-μm silicate emission ever observed for an active galactic nucleus (AGN), we discovered SAGE0534AGN (z ∼ 1.01), a similar AGN but with less extreme silicate emission. Both were originally mistaken as evolved stars in the Magellanic Clouds. Lack of far-infrared emission, and therefore star formation, implies we are seeing the central engine of the AGN without contribution from the host galaxy. They could be a key link in galaxy evolution. We used a dimensionality reduction algorithm, t-distributed stochastic neighbour embedding with multiwavelength data from Gaia EDR3, VISTA survey of the Magellanic Clouds, AllWISE, and the Australian Square Kilometre Array Pathfinder to find these two unusual AGNs are grouped with 16 other objects separated from the rest, suggesting a rare class. Our spectroscopy at South African Astronomical Observatory/Southern African Large Telescope and literature data confirm at least 14 of these objects are extragalactic (0.13 < z < 1.23), all hosting AGN. Using spectral energy distribution fitter C igale we find that the majority of dust emission ($\gt 70 {{\ \rm per\ cent}}$) in these sources is due to the AGN. Host galaxies appear to be either in or transitioning into the green valley. There is a trend of a thinning torus, increasing X-ray luminosity, and decreasing Eddington ratio as the AGN transition through the green valley, implying that as the accretion supply depletes, the torus depletes and the column density reduces. Also, the near-infrared variability amplitude of these sources correlates with attenuation by the torus, implying the torus plays a role in the variability.
Quasi-periodic Gaussian processes for stellar activity: From physical to kernel parameters
Authors: Nicholson B A , Aigrain S
Published: July 2022

In recent years, Gaussian Process (GP) regression has become widely used to analyse stellar and exoplanet time-series data sets. For spotted stars, the most popular GP covariance function is the quasi-periodic (QP) kernel, whose hyperparameters of the GP have a plausible interpretation in terms of physical properties of the star and spots. In this paper, we test the reliability of this interpretation by modelling data simulated using a spot model using a QP GP, and the recently proposed quasi-periodic plus cosine (QPC) GP, comparing the posterior distributions of the GP hyperparameters to the input parameters of the spot model. We find excellent agreement between the input stellar rotation period and the QP and QPC GP period, and very good agreement between the spot decay time-scale and the length scale of the squared exponential term. We also compare the hyperparameters derived from light and radial velocity (RV) curves for a given star, finding that the period and evolution time-scales are in good agreement. However, the harmonic complexity of the GP, while displaying no clear correlation with the spot properties in our simulations, is systematically higher for the RV than for the light-curve data. Finally, for the QP kernel, we investigate the impact of noise and time-sampling on the hyperparameters in the case of RVs. Our results indicate that good coverage of rotation period and spot evolution time-scales is more important than the total number of points, and noise characteristics govern the harmonic complexity.
The initial magnetic criticality of pre-stellar cores
Authors: Priestley Felix D , Yin Charles , Wurster James
Published: July 2022

Direct observational measurements of the magnetic field strength in pre-stellar cores typically find supercritical mass-to-flux ratios, suggesting that the magnetic field is insufficient to prevent gravitational collapse. These measurements suffer from significant uncertainties; an alternative approach is to utilize the sensitivity of pre-stellar chemistry to the evolutionary history, and indirectly constrain the degree of magnetic support. We combine non-ideal magnetohydrodynamic simulations of pre-stellar cores with time-dependent chemistry and radiative transfer modelling, producing synthetic observations of the model cores in several commonly observed molecular lines. We find that molecules strongly affected by freeze-out, such as CS and HCN, typically have much lower line intensities in magnetically subcritical models compared to supercritical ones, due to the longer collapse time-scales. Subcritical models also produce much narrower lines for all species investigated. Accounting for a range of core properties, ages, and viewing angles, we find that supercritical models are unable to reproduce the distribution of CS and N2H+ line strengths and widths seen in an observational sample, whereas subcritical models are in good agreement with the available data. This suggests that despite presently having supercritical mass-to-flux ratios, pre-stellar cores form as magnetically subcritical objects.
RS3PE syndrome: Autoinflammatory features of a rare disorder
Authors: Borges Tiago , Silva Sérgio
Published: July 2022

Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome was first described by McCarty in 1985 and is characterized by pitting oedema and an acute symmetrical synovitis of small joints. Self-directed inflammation in autoimmune disorders is caused by an abnormal activation of the adaptive immune system, while in autoinflammatory disorders, it is due to aberrant activation of the innate immune system without autoantibodies or autoreactive T cells. The role of autoimmunity in the pathogenesis of RS3PE syndrome is suggested by possible associations with some autoimmune diseases and human leukocyte antigen (HLA) haplotypes. However, several other features point to a possible role of autoinflammation in RS3PE syndrome. In this review, the relative contributions of both innate and adaptive immune systems to the pathogenesis of RS3PE syndrome are discussed.
MPP6 stimulates both RRP6 and DIS3 to degrade a specified subset of MTR4-sensitive substrates in the human nucleus
Authors: Fujiwara Naoko , Shigemoto Maki , Hirayama Mizuki , Fujita Ken-ichi , Seno Shigeto , Matsuda Hideo , Nagahama Masami , Masuda Seiji
Published: July 2022

Recent in vitro reconstitution analyses have proven that the physical interaction between the exosome core and MTR4 helicase, which promotes the exosome activity, is maintained by either MPP6 or RRP6. However, knowledge regarding the function of MPP6 with respect to in vivo exosome activity remains scarce. Here, we demonstrate a facilitative function of MPP6 that composes a specific part of MTR4-dependent substrate decay by the human exosome. Using RNA polymerase II-transcribed poly(A)+ substrate accumulation as an indicator of a perturbed exosome, we found functional redundancy between RRP6 and MPP6 in the decay of these poly(A)+ transcripts. MTR4 binding to the exosome core via MPP6 was essential for MPP6 to exert its redundancy with RRP6. However, at least for the decay of our identified exosome substrates, MTR4 recruitment by MPP6 was not functionally equivalent to recruitment by RRP6. Genome-wide classification of substrates based on their sensitivity to each exosome component revealed that MPP6 deals with a specific range of substrates and highlights the importance of MTR4 for their decay. Considering recent findings of competitive binding to the exosome between auxiliary complexes, our results suggest that the MPP6-incorporated MTR4-exosome complex is one of the multiple alternative complexes rather than the prevailing one.
Structural assembly of the nucleic-acid-binding Thp3–Csn12–Sem1 complex functioning in mRNA splicing
Authors: Kuang Zhiling , Ke Jiyuan , Hong Jiong , Zhu Zhongliang , Niu Liwen
Published: July 2022

PCI domain proteins play important roles in post-transcriptional gene regulation. In the TREX-2 complex, PCI domain-containing Sac3 and Thp1 proteins and accessory Sem1 protein form a ternary complex required for mRNA nuclear export. In contrast, structurally related Thp3–Csn12–Sem1 complex mediates pre-mRNA splicing. In this study, we determined the structure of yeast Thp3186–470–Csn12–Sem1 ternary complex at 2.9 Å resolution. Both Thp3 and Csn12 structures have a typical PCI structural fold, characterized by a stack of α-helices capped by a C-terminal winged-helix (WH) domain. The overall structure of Thp3186–470–Csn12–Sem1 complex has an inverted V-shape with Thp3 and Csn12 forming the two sides. A fishhook-shaped Sem1 makes extensive contacts on Csn12 to stabilize its conformation. The overall structure of Thp3186–470–Csn12–Sem1 complex resembles the previously reported Sac3–Thp1–Sem1 complex, but also has significant structural differences. The C-terminal WH domains of Thp3 and Csn12 form a continuous surface to bind different forms of nucleic acids with micromolar affinity. Mutation of the basic residues in the WH domains of Thp3 and Csn12 affects nucleic acid binding in vitro and mRNA splicing in vivo. The Thp3–Csn12–Sem1 structure provides a foundation for further exploring the structural elements required for its specific recruitment to spliceosome for pre-mRNA splicing.
TET1 regulates gene expression and repression of endogenous retroviruses independent of DNA demethylation
Authors: Stolz Paul , Mantero Angelo Salazar , Tvardovskiy Andrey , Ugur Enes , Wange Lucas E , Mulholland Christopher B , Cheng Yuying , Wierer Michael , Enard Wolfgang , Schneider Robert , Bartke Till , Leonhardt Heinrich , Elsässer Simon J , Bultmann Sebastian
Published: July 2022

DNA methylation (5-methylcytosine (5mC)) is critical for genome stability and transcriptional regulation in mammals. The discovery that ten-eleven translocation (TET) proteins catalyze the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) revolutionized our perspective on the complexity and regulation of DNA modifications. However, to what extent the regulatory functions of TET1 can be attributed to its catalytic activity remains unclear. Here, we use genome engineering and quantitative multi-omics approaches to dissect the precise catalytic vs. non-catalytic functions of TET1 in murine embryonic stem cells (mESCs). Our study identifies TET1 as an essential interaction hub for multiple chromatin modifying complexes and a global regulator of histone modifications. Strikingly, we find that the majority of transcriptional regulation depends on non-catalytic functions of TET1. In particular, we show that TET1 is critical for the establishment of H3K9me3 and H4K20me3 at endogenous retroviral elements (ERVs) and their silencing that is independent of its canonical role in DNA demethylation. Furthermore, we provide evidence that this repression of ERVs depends on the interaction between TET1 and SIN3A. In summary, we demonstrate that the non-catalytic functions of TET1 are critical for regulation of gene expression and the silencing of endogenous retroviruses in mESCs.
FACT subunit SUPT16H associates with BRD4 and contributes to silencing of interferon signaling
Authors: Zhou Dawei , Wu Zhenyu , Park Jun-Gyu , Fiches Guillaume N , Li Tai-Wei , Ma Qin , Huang Huachao , Biswas Ayan , Martinez-Sobrido Luis , Santoso Netty G , Zhu Jian
Published: July 2022

FACT (FAcilitates Chromatin Transcription) is a heterodimeric protein complex composed of SUPT16H and SSRP1, and a histone chaperone participating in chromatin remodeling during gene transcription. FACT complex is profoundly regulated, and contributes to both gene activation and suppression. Here we reported that SUPT16H, a subunit of FACT, is acetylated in both epithelial and natural killer (NK) cells. The histone acetyltransferase TIP60 contributes to the acetylation of SUPT16H middle domain (MD) at lysine 674 (K674). Such acetylation of SUPT16H is recognized by bromodomain protein BRD4, which promotes protein stability of SUPT16H in both epithelial and NK cells. We further demonstrated that SUPT16H-BRD4 associates with histone modification enzymes (HDAC1, EZH2), and further regulates their activation status and/or promoter association as well as affects the relevant histone marks (H3ac, H3K9me3 and H3K27me3). BRD4 is known to profoundly regulate interferon (IFN) signaling, while such function of SUPT16H has never been explored. Surprisingly, our results revealed that SUPT16H genetic knockdown via RNAi or pharmacological inhibition by using its inhibitor, curaxin 137 (CBL0137), results in the induction of IFNs and interferon-stimulated genes (ISGs). Through this mechanism, depletion or inhibition of SUPT16H is shown to efficiently inhibit infection of multiple viruses, including Zika, influenza, and SARS-CoV-2. Furthermore, we demonstrated that depletion or inhibition of SUPT16H also causes the remarkable activation of IFN signaling in NK cells, which promotes the NK-mediated killing of virus-infected cells in a co-culture system using human primary NK cells. Overall, our studies unraveled the previously un-appreciated role of FACT complex in coordinating with BRD4 and regulating IFN signaling in both epithelial and NK cells, and also proposed the novel application of the FACT inhibitor CBL0137 to treat viral infections.
sRNA-controlled iron sparing response in Staphylococci
Authors: Coronel-Tellez Rodrigo H , Pospiech Mateusz , Barrault Maxime , Liu Wenfeng , Bordeau Valérie , Vasnier Christelle , Felden Brice , Sargueil Bruno , Bouloc Philippe
Published: July 2022

Staphylococcus aureus, a human opportunist pathogen, adjusts its metabolism to cope with iron deprivation within the host. We investigated the potential role of small non-coding RNAs (sRNAs) in dictating this process. A single sRNA, named here IsrR, emerged from a competition assay with tagged-mutant libraries as being required during iron starvation. IsrR is iron-repressed and predicted to target mRNAs expressing iron-containing enzymes. Among them, we demonstrated that IsrR down-regulates the translation of mRNAs of enzymes that catalyze anaerobic nitrate respiration. The IsrR sequence reveals three single-stranded C-rich regions (CRRs). Mutational and structural analysis indicated a differential contribution of these CRRs according to targets. We also report that IsrR is required for full lethality of S. aureus in a mouse septicemia model, underscoring its role as a major contributor to the iron-sparing response for bacterial survival during infection. IsrR is conserved among staphylococci, but it is not ortholog to the proteobacterial sRNA RyhB, nor to other characterized sRNAs down-regulating mRNAs of iron-containing enzymes. Remarkably, these distinct sRNAs regulate common targets, illustrating that RNA-based regulation provides optimal evolutionary solutions to improve bacterial fitness when iron is scarce.
Stochastically multimerized ParB orchestrates DNA assembly as unveiled by single-molecule analysis
Authors: Guo Lijuan , Zhao Yilin , Zhang Qian , Feng Ying , Bi Lulu , Zhang Xia , Wang Teng , Liu Cong , Ma Hanhui , Sun Bo
Published: July 2022

The tripartite ParABS system mediates chromosome segregation in a wide range of bacteria. Dimeric ParB was proposed to nucleate on parS sites and spread to neighboring DNA. However, how properly distributed ParB dimers further compact chromosomal DNA into a higher-order nucleoprotein complex for partitioning remains poorly understood. Here, using a single-molecule approach, we show that tens of Bacillus subtilis ParB (Spo0J) proteins can stochastically multimerize on and stably bind to nonspecific DNA. The introduction of CTP promotes the formation and diffusion of the multimeric ParB along DNA, offering an opportunity for ParB proteins to further forgather and cluster. Intriguingly, ParB multimers can recognize parS motifs and are more inclined to remain immobile on them. Importantly, the ParB multimer features distinct capabilities of not only bridging two independent DNA molecules but also mediating their transportation, both of which are enhanced by the presence of either CTP or parS in the DNA. These findings shed new light on ParB dynamics in self-multimerization and DNA organization and help to better comprehend the assembly of the ParB-DNA partition complex.
Single-cell analysis reveals an Angpt4-initiated EPDC-EC-CM cellular coordination cascade during heart regeneration
Authors: Wu Zekai , Shi Yuan , Cui Yueli , Xing Xin , Zhang Liya , Liu Da , Zhang Yutian , Dong Ji , Jin Li , Pang Meijun , Xiao Rui-Ping , Zhu Zuoyan , Xiong Jing-Wei , Tong Xiangjun , Zhang Yan , Wang Shiqiang , Tang Fuchou , Zhang Bo
Published: July 2022

Mammals exhibit limited heart regeneration ability, which can lead to heart failure after myocardial infarction. In contrast, zebrafish exhibit remarkable cardiac regeneration capacity. Several cell types and signaling pathways have been reported to participate in this process. However, a comprehensive analysis of how different cells and signals interact and coordinate to regulate cardiac regeneration is unavailable. We collected major cardiac cell types from zebrafish and performed high-precision single-cell transcriptome analyses during both development and post-injury regeneration. We revealed the cellular heterogeneity as well as the molecular progress of cardiomyocytes during these processes, and identified a subtype of atrial cardiomyocyte exhibiting a stem-like state which may transdifferentiate into ventricular cardiomyocytes during regeneration. Furthermore, we identified a regeneration-induced cell (RIC) population in the epicardium-derived cells (EPDC), and demonstrated Angiopoietin 4 (Angpt4) as a specific regulator of heart regeneration. angpt4 expression is specifically and transiently activated in RIC, which initiates a signaling cascade from EPDC to endocardium through the Tie2-MAPK pathway, and further induces activation of cathepsin K in cardiomyocytes through RA signaling. Loss of angpt4 leads to defects in scar tissue resolution and cardiomyocyte proliferation, while overexpression of angpt4 accelerates regeneration. Furthermore, we found that ANGPT4 could enhance proliferation of neonatal rat cardiomyocytes, and promote cardiac repair in mice after myocardial infarction, indicating that the function of Angpt4 is conserved in mammals. Our study provides a mechanistic understanding of heart regeneration at single-cell precision, identifies Angpt4 as a key regulator of cardiomyocyte proliferation and regeneration, and offers a novel therapeutic target for improved recovery after human heart injuries.
Treatment for Mild Chronic Hypertension During Pregnancy
Authors: Tita Alan T. , Szychowski Jeff M. , Boggess Kim , Dugoff Lorraine , Sibai Baha , Lawrence Kirsten , Hughes Brenna L. , Bell Joseph , Aagaard Kjersti , Edwards Rodney K. , Gibson Kelly , Haas David M. , Plante Lauren , Metz Torri , Casey Brian , Esplin Sean , Longo Sherri , Hoffman Matthew , Saade George R. , Hoppe Kara K. , Foroutan Janelle , Tuuli Methodius , Owens Michelle Y. , Simhan Hyagriv N. , Frey Heather , Rosen Todd , Palatnik Anna , Baker Susan , August Phyllis , Reddy Uma M. , Kinzler Wendy , Su Emily , Krishna Iris , Nguyen Nicki , Norton Mary E. , Skupski Daniel , El-Sayed Yasser Y. , Ogunyemi Dotum , Galis Zorina S. , Harper Lorie , Ambalavanan Namasivayam , Geller Nancy L. , Oparil Suzanne , Cutter Gary R. , Andrews William W.
Published: July 2022

(Abstracted from N Engl J Med 2022;386:1781–1792)

Chronic hypertension develops in 2% of pregnancies in the United States. As this condition disproportionately affects Black women and is associated with 3 to 5 times the risk of placental abruption, preeclampsia, preterm birth (PTB), small-for-gestational-age (SGA) birthweight, and perinatal death, optimizing treatment is critical to possibly preventing these associated complications.
Health Disparities in Uterine Cancer: Report From the Uterine Cancer Evidence Review Conference
Authors: Whetstone Sara , Burke William , Sheth Sangini S. , Brooks Rebecca , Cavens Arjeme , Huber-Keener Kathryn , Scott Dana M. , Worly Brett , Chelmow David
Published: July 2022

(Abstracted from Obstet Gynecol 2022;139:645–659)

The American College of Obstetricians and Gynecologists (ACOG) convened a panel of experts to develop evidence-based educational materials for clinicians on health disparities in the treatment, diagnosis, and outcomes for uterine cancer. Based on reviews of the literature, best practices, and guidelines, the panel identified substantive inequities and provided guidance for future research.
A comparison of the efficacy of dutasteride on reducing lower urinary tract symptoms among patients with small versus large benign prostatic hyperplasia
Authors: Shigehara Kazuyoshi , Kato Yuki , Kawaguchi Shohei , Izumi Kouji , Kadono Yoshifumi , Mizokami Atsushi
Published: July 2022

Background

Only a few reports have currently studied the efficacy of dutasteride in patients with small benign prostatic hyperplasia (BPH). We investigated the efficacy of dutasteride on reducing lower urinary tract symptoms among them.

Materials and methods

A total of 81 patients with BPH who completed 52weeks of 0.5?mg dutasteride treatment were enrolled. Each patient filled out the International Prostatic Symptom Score (IPSS) and overactive bladder symptom score (OABSS) at baseline and at the 6- and 12-month follow-up visits. Total testosterone, prostate-specific antigen, adenoma/prostate volume (PV), uroflowmetry analysis, and postvoid residual volume were evaluated at baseline and at the 12-month follow-up visit. The enrolled patients were divided into 2 groups according to PV at baseline. The groups were as follows: Group A (PV ≥ 30 mL) and Group B (PV < 30 mL).

Results

Groups A and B had mean PVs of 52.1 and 23.6 mL and mean IPSS scores of 16.7 and 14.4, respectively. Group A had significantly higher OABSS and prostate-specific antigen levels at baseline than Group B, while no significant differences in any other baseline characteristics was observed. After dutasteride treatment, adenoma volume and PV decreased significantly, while testosterone level showed a significant increase in both groups. Group A showed significant improvements in the total IPSS, voiding and storage subscore of the IPSS, OABSS, maximum flow rate, and postvoid residual volume. Group B, on the other hand, also showed significant improvements only in the total IPSS, voiding subscore of the IPSS, and maximum flow rate.

Conclusions

The present study suggests a possible beneficial effect of dutasteride treatment on the reduction of lower urinary tract symptoms in patients with small and large BPH. However, the effectiveness of dutasteride was limited compared to patients with large BPH (PV ≥ 30 mL).
The “ins and outs” of the magnetic ureteral stent: A novel innovation in Endourology
Authors: Damodaran Vishal , Els Brandon , Daras Efthimia , Kataka Tracy , Gulamali Sadiyabanu Safiq , Ntakana S’babalwe , Perera Marlon , Adam Ahmed
Published: July 2022

Background

Ureteral stents play a major role in maintaining ureteral patency. Various innovations are advocated in the design and subsequent removal of traditional double-J ureteral stents, such as the magnetic-end double-J ureteral stent (MEDJUS). This stent facilitates outpatient removal using a magnetic stent removal device. This systematic review was conducted to analyze the published role, efficacy, and outcomes of MEDJUS.

Materials and methods

After PROSPERO registration (CRD42021235739), an electronic database search (PubMed, EMBASE, Cochrane Library, Scopus, and Web of Science) was performed on December 31, 2020. The search terms were as follows: “magnetic,” “ureteric,” “stent,” “double-J,” “urotech,” and “Black-Star.”

Results

Nine studies with a total of 685 patients were included in the systematic review. The total number of MEDJUS procedures used was 498 (73%) compared to the 187 (27%) traditional double-J stent method. Magnetic-end double-J ureteral stent extraction failure was reported in 8 cases (1.61%). Compared with traditional stents, MEDJUS showed a cost benefit in 5/5 studies. Better pain scores (during stent in situ) and (at stent removal) were observed in 2/3 and 3/4 of the studies, respectively.

Conclusions

Magnetic-end double-J ureteral stent may serve as a viable alternative to traditional double-J stents, offering cost and pain benefits with similar rates of complications. Magnetic-end double-J ureteral stent also offers relative ease of extraction and a reduced need for inpatient removal. This ambulatory stent removal technique has forged its use in modern urological practice.
How Risk Management During COVID-19 Influences Eldercare Personnel's Perceptions of Their Work Environment
Authors: Rueskov Poulsen Vivian , Juul Nilsson Charlotte , Balle Hansen Morten , Bredal Charlotte , Juul-Madsen Maria , Nabe-Nielsen Kirsten
Published: July 2022

Objective

To investigate the association between workplace COVID-19 (coronavirus disease 2019) risk management and eldercare workers' perception of their social environment at work.

Methods

Cross-sectional questionnaire data from 952 participants were collected by the Danish labor union, FOA, and analyzed using multinomial logistic regression.

Results

Unclear guidelines, insecurity regarding organization of work, lack of attention to vulnerable employees, and lack of instruction in the use of personal protective equipment were associated with perceived negative changes in the social environment at work. Also, higher local incidence rates of SARS-CoV-2 infections were associated with a weaker sense of community (odds ratio, 1.18; 95% confidence interval, 1.04–1.36).

Conclusions

These findings indicate that risk management is important not only for prevention of infection but also for individual and workplace resilience toward external demands and health threats.
Physical Exertion Partially Mitigates Task-Switching Deficits From Sleep Loss
Authors: Stepan Michelle E. , Wilckens Kristine A. , Hostler David , Wallace Meredith L. , Franzen Peter L.
Published: July 2022

Objective

The aim of the study is to investigate effects of physical exertion on cognitive deficits from sleep loss under conditions that mimic a firefighting scenario.

Methods

Twenty-four male participants completed a crossover study design with 3 conditions: total sleep deprivation, sleep disruption (three 60-minute awakenings), and rested control. Participants then completed 50 minutes of a physical exertion task involving treadmill exercise in a heated room while wearing firefighter protective clothing. Vigilant attention and task-switching performance were assessed pre– and post–sleep manipulation and pre– and post–physical exertion. Vigilant attention was also assessed mid–physical exertion.

Results

Total sleep deprivation and sleep disruption increased attentional lapses and task-switching RT. Total sleep deprivation additionally reduced task-switching accuracy. Performance after physical exertion improved only for task-switching RT after total sleep deprivation.

Conclusions

Physical exertion selectively mitigated task-switching RT deficits from the most severe sleep loss condition, total sleep deprivation.