bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction for the Multi-band Afterglows of FRB 200428 and its Implication
Authors: Du Mei , Yi Shuang-Xi , Deng Can-Min , Wang Pei
Published: August 2023

The physical mechanism of fast radio bursts (FRBs) is still unknown. On 2020 April 28, a special radio burst, FRB 200428, was detected and believed to be associated with the Galactic magnetar SGR 1935+2154. It confirms that at least some of the FRBs were generated by magnetars, although the radiation mechanism continues to be debated. To this end, we study in detail the multiband afterglows of FRB 200428 described by the synchrotron fireball shock model. We find the prediction for the optical and radio afterglows of FRB 200428 is consistent with the observations when considering the post-FRB optical and radio upper limits from the literature. We also show that the follow up detection of the afterglows from fast radio bursts like—FRB 200428 is possible at the radio band, though challenging. Based on our model, one can obtain information about the energy of the fireball, the radiation zone, and the nature of the surrounding medium. That may shed light on the physical mechanism of FRBs.
Resonance in radio frequency sheath admittance and enhanced impurity emission near the ion cyclotron frequency
Authors: Rezazadeh Mikhail , Myra James R. , Curreli Davide
Published: August 2023

Ion cyclotron resonance heating (ICRH) is of considerable interest among all auxiliary heating techniques, because it transfers power directly to ions, targets the high-density core, and involves the cheapest radio-frequency (RF) components. During ICRH operation, RF sheaths form on the ICRH antenna itself, nearby hardware, and far-field surfaces. These sheaths are associated with large hot-spot formation and impurity emissions. This work presents high-resolution numerical modelling of RF sheaths in nuclear fusion scenarios using hPIC2, a Debye-scale particle-in-cell code. The modelling reveals a new RF sheath phenomenon which occurs when the RF is resonant with a species ion cyclotron frequency or harmonic in an oblique magnetic field. This resonance of the RF sheath causes modifications of the energy-angle distributions of the ions impacting on the walls, with consequent increase in wall impurity emission. Due to the

1

/

R

scaling of the magnetic field in a tokamak, such cases are possible on divertor or vacuum chamber surfaces, depending on the geometry of the tokamak and the RF heating scenario. A simple physics interpretation using a driven damped harmonic oscillator is proposed, where the ion sheath transit time plays the role of damping the RF sheath admittance. Critically, the resonance leads to increased ion heat flux at the wall as well as increased physical sputtering, despite a lack of increase in RF rectified sheath potential.
Systematic design of a multi-input multi-output controller by model-based decoupling: a demonstration on TCV using multi-species gas injection
Authors: Koenders J.T.W. , Perek A. , Galperti C. , Duval B.P. , Février O. , Theiler C. , van Berkel M. ,   the TCV Team
Published: August 2023

In this paper, we present the first results of a systematically designed multi-input multi-output gas-injection controller on Tokamak á Configuration Variable (TCV). We demonstrate the simultaneous real-time control of the NII emission front position and line-integrated electron density using nitrogen and deuterium gas injection. Injection of nitrogen and/or deuterium affects both the NII emission front position and line-integrated electron density. This interplay between control loops is termed interaction and, when strongly present, makes designing a controller a significantly more complex problem. Interaction between the control loops can be reduced to an acceptable level by redefining inputs, decoupling the multi-input multi-output control problem to separated single-input single-output problems. We demonstrate how to achieve this by defining virtual control inputs from linear combinations of the actuators available. For the demonstration on TCV, linear combinations of deuterium and nitrogen gas injection are computed from transfer-function models to obtain these virtual inputs. The virtual inputs reduce the interaction in the control-relevant frequency range to a point where control of the NII emission front position and line-integrated electron density can be considered decoupled, allowing for the much simpler design of single-input single-output controllers for each loop. Implementing the controllers with the virtual inputs gives the multi-input multi-output gas-injection controller. This approach is well established in the control community, and is presented here as a demonstration to drive developments of multi-input multi-output control strategies. In particular, the envisioned control of particle- and heat fluxes impacting the divertor targets by injection of multiple gas species.
Using the Stix finite element RF code to investigate operation optimization of the ICRF antenna on Alcator C-Mod
Authors: Migliore C. , Wright J.C. , Stowell M. , Bonoli P.T.
Published: August 2023

As the Ion Cyclotron Radio Frequency range (ICRF) heating becomes more favorable in fusion devices, the urgency of predicting and mitigating impurity generation that arises from it becomes more pressing. In the ICRF regime, rectified Radio Frequency (RF) sheaths are known to form at antenna and material edges that influence negative effects like sputtering and a decrease in heating efficiency. Methods to mitigate the formation of these RF sheaths through RF image currents cancellation have been experimentally studied. A power-phasing scan done on Alcator C-Mod in which the amount of power on the two inner straps (P
in) versus the total 4 straps (P
tot) was varied showed a minimization of enhanced potentials between

P

in

/

P

tot

∼

0.7–0.9 while impurities were minimized for

P

in

/

P

tot

∼

0.5–0.8. New capabilities in the realm of representing the RF sheath numerically now allow for these experiments to be simulated. Given the size of the sheath relative to the scale of the device, it can be approximated as a Boundary Condition (BC). A new parallelized cold-plasma wave equation solver called Stix implements a non-linear sheath impedance model BC formulated by Myra et al (2015 Phys. Plasmas
22 062507) through the method of finite elements using the MFEM library [http://mfem.org]. It is seen that Stix shows qualitative agreement with the measured C-Mod enhanced potentials.
Effects of toroidally-distributed-divertor biasing on scrape-off-layer (SOL) current drive, divertor particle flux and fast electron confinement in the QUEST spherical tokamak
Authors: Toi Kazuo , Onchi Takumi , Zushi Hideki , Kuroda Kengoh , Idei Hiroshi , Hanada Kazuaki , Hasegawa Makoto , Kojima Shinichiro , Ikezoe Ryuya , Ido Takeshi , Kawasaki Shoji , Higashijima Aki ,   QUEST Experiment Group
Published: August 2023

A novel divertor biasing by four biasing plates distributed toroidally (TDDB) on the upper divertor target plate is applied to low density tokamak plasmas started-up by 28 GHz 2nd harmonic electron cyclotron current drive (ECCD) in a quasi-double null configuration of the QUEST spherical tokamak (ST). In the ST plasmas of line averaged electron density <

n
e

> ∼0.7–1 × 1018 m−3, about 20%–40% of the current

I

bias

driven by ∼85 V sawtooth bias voltage reaches the lower divertor plate along the biased scrape-off-layer (SOL) flux tube as the SOL current

I

SOL

. The fact

I

SOL

is noticeably lower than

I

bias

 

indicates an appreciable leakage of parallel current from the biased SOL flux tube. The leakage currents in the toroidal and radial directions are confirmed by detection of them using the unbiased plates in the TDDB experiments. From the ion saturation current density profile obtained by a divertor Langmuir probe array, the fall-off lengths of divertor particle flux are estimated together with the strike line position. Total particle flux to the upper divertor, evaluated by the integrated ion saturation current density profile is reduced by up to 45% during positive biasing of the TDDB, depending on the position of the strike line to the biased plate. In addition, the TDDB also induces a noticeable loss of fast electrons produced by ECCD, leading to an ∼2% reduction in the maximum toroidal current of the ST plasma compared to a shot without the TDDB. Reduction of the divertor particle flux and enhancement of the fast electron losses are thought to be dominantly caused by E

×
B

drift induced by the TDDB. In the present experimental conditions, the effects of magnetic perturbations produced by the SOL currents on the fast electron losses can be neglected because of a too small SOL current.
Characteristics and causes of voltage observed at the current feeder of high-temperature superconducting WISE conductor
Authors: Narushima Y , Garfias-Davalos D , Onodera Y , Hamaguchi S , Chikaraishi H , Yanagi N , Baba T , Miyazawa J
Published: August 2023

The HTS (high-temperature superconducting) conductor is a feasible candidate for constructing magnets for next-generation fusion devices because of its higher critical current in a high magnetic field. A new concept of the HTS-WISE (Wound and Impregnated Stacked Elastic tapes) conductor has been studied aiming to apply the fusion reactor magnet. Here, the WISE-U conductor is composed of stacked thirty REBCO tapes (10 mm width, 65 μm thickness, I
c = 370 A @77 K, s.f.) wrapped by a stainless-steel coil tube which is inserted into the metal pipe. The 4 m-long REBCO tapes are folded with a radius of curvature of 35 mm in a hairpin-like structure. A low-melting-point metal U-Alloy 60 whose melting point is 60°C is poured into the pipe for impregnation to make the non-insulation conductor. The REBCO tapes and the current feeder made of oxygen-free copper were also impregnated with the U-Alloy 60 to connect. This fabrication method has the advantage of being easier to fabricate than the technique of connecting each tape using indium foil. The energization test results showed that a maximum current value of 16.9 kA was recorded at B = 5 T and T = 30 K, however, a burnout occurred in the current feeder before the critical current was determined. Then, the improved WISE conductor has been designed and tested which showed a maximum of 19kA was reached in the self-field and 20K. However, burnout still occurred in the current feeder section. In those experiments, the superconducting section has not been damaged at all. If this burnout had been avoided, a higher current-carrying capacity could have been obtained. Identifying the cause of burnout and improving the current feeder is required.
X-ray Characterizations of Iron-based Superconductor Round Wires with Large Critical Current Density
Authors: Tamegai T , Pyon S , Sasaki T , Ito T , Sakagami R , Awaji S , Kajitani H
Published: August 2023

Characterizations of round wires of iron-based superconductors were performed by using two different X-ray techniques. The core of the round wire turns out to be concentrically textured. The texturing parameter (r) defined by r = I(002)/I(103) has a clear correlation with the value of the critical current density (J
c) of the wire. Using ~18 m-long (Ba,A)Fe2As2 (A: K, Na) wires, small magnets was constructed and successfully generated a magnetic field as large as 3.1 kOe at I = 53 A. The wire for the magnet was carefully cut and local variation of the critical current (I
c) was evaluated. Variation of the core area was also measured by using X-ray tomography for the segments with the largest and smallest I
c. Obtained images demonstrates that the core has a certain degree of sausaging effect and it has good correlation with I
c of the wire. Using the largest value of measured I
c and the minimum core area of that segment, record-high value of J
c = 71 kA/cm2 at 100 kOe has been achieved.
Effect of nano ZrO2 addition on the properties of Ca0.86Sr0.14CuO2 added Bi 2223 composites
Authors: Verma Pawan K , Rajasekharan T. , Das Shamili C , Surendran K P , Seshu Bai V
Published: August 2023

Effect of introducing nano ZrO2 particles into (Ca,Sr)CuO2 added Bi 2223 superconductor composites is studied. Microstructures revealed that 20 mol. % (Ca,Sr)CuO2 phase added to Bi 2223 formed as micron sized particles among the Bi 2223 platelet shaped grains. Distribution of (Ca,Sr)CuO2 in Bi 2223 has enhanced the critical current density (Jc) and flux pinning force density (Fp ) substantially to fields up to 9 T at 20 K. Introduction of nano ZrO2 into the composite reacted with (Ca,Sr)CuO2 particles and formed additional secondary phases of increasing amount with a rise in ZrO2 content. This resulted in lowering of Jc(0) due to a gradual reduction in the fraction of superconducting phases, but retained the enhanced field range in which flux pinning was achieved. At 10 wt.% addition of ZrO2, Bi 2223 phase was suppressed, and Bi 2212 phase was promoted. Scaling behaviour of pinning force density has shown the dominant mechanism at low fields to be normal surface pinning due to interfacial defects. The fact that (Ca,Sr)CuO2 distributes itself as fine spherical particles in Bi 2223, without causing degradation of the superconducting matrix material, is of significance and opens up a scope to optimize the microstructures further for enhancement of flux pinning.
Yoke geometry study using pulsed field magnetization on superconducting joined bulk Gd-Ba-Cu-O
Authors: Takemura K , Sudo K , Dorget R , Dadiel J L , Sakafuji M , Yokoyama K , Oka T , Sakai N
Published: August 2023

Conditions for obtaining high-quality superconducting joint in Gd-Ba-Cu-O bulk superconductors were investigated, and the effects of PFM properties of the joined bulk and the change of yoke geometry in magnetization were examined. For a good superconducting joint fabricated by the local melting method using sintered Er-Ba-Cu-O, the J
c-B property and multiple Hall sensors indicates that the joined part is the preferential field penetration path. PFM was performed using a changed geometry of yoke in which concentrated long pulse to the joined part, but the result was equivalent to the trapped field before the changing yoke because the volume of the yoke was reduced. This is the first attempt to approach an effective PFM method for the joined bulk from the viewpoint of a changed geometry of yoke.
Accuracy Improvement of Polynomial Computing RSFQ Circuits Based on Stochastic Computing by Partial Duplication
Authors: Tsuji Moeka , Kito Nobutaka
Published: August 2023

This study proposes a design method for RSFQ stochastic computing (SC) circuits. The method generates circuits with improved accuracy compared to a previously proposed method. This improvement in accuracy is realized using partial duplication. SC requires a large number of clock cycles to obtain a calculation result owing to lengthy observation of the output bitstream. The proposed method can either enhance the accuracy while maintaining the latency or mitigate the latency in clock cycles while maintaining the same accuracy. The design method duplicates a small part of the original circuit considering effectiveness for accuracy improvement. Therefore, the number of additional gates in circuits designed with the proposed method is negligible. The evaluation results indicate that, compared to circuits without duplication, the mean absolute error of circuits including one duplicated part designed with the method is reduced to approximately 60%.
Design Study of an HTS Linear Power Generator Suitable for Wave Energy Converter
Authors: Kambo Petrus , Yamanouchi Yuhi , Caunes Antomne A , Yamaguchi Kota , Izumi Mitsuru , Ida Tetsuya
Published: August 2023

In this paper, we show a conceptual structure of a direct drive linear power generator with REBaCuO high-temperature superconducting (HTS) bulk field poles for wave energy conversion. The proposed linear power generator structure is comprised of a moving armature coil and HTS bulks concept, which we call it a dual translator power generation system. Its performance has been analyzed using a finite-element electromagnetic field analysis method. A determination of the main machine parameters for the dual translator HTS linear power generator was conducted. Simulation results were compared between our dual translator HTS linear generator structure and the use of permanent magnets (PMs) for the field poles of that structure. It was found that the electromotive forces, electromagnetic forces and output power of the dual translator HTS linear power generator structure are 1.67, 2.63 and 2.60 times superior to that of dual translator PM linear generator structure, respectively. A combination of the dual translator power generation system and HTS bulks has the potential to help us to achieve higher torque and higher output power despite low ocean wave speed, which is important to achieve practical application of ocean power generation systems.
Development of Exciter System for Power Supply driven HTS-MRI
Authors: Shirai Yasuyuki , Uchida Yuto , Miura Hideaki , Hattori Taisuke , Matsuda Tetsuya
Published: August 2023

Exciter systems is examined for helium free high-temperature superconducting (HTS)-MRI magnet. We have developed an active magnetic field stability control by use of a highly stabilized power supply instead of the persistent current operation. The magnetic field stability was measured and evaluated using a HTS-MRI test magnet under the power supply driving mode of a dropper-type and of a switching-type direct-current exciter system. A high stable direct current power supply is normally designed using the dropper-type power supply which is suitable for constant current operation of less current ripple. However, it is of large power loss and is not suitable for charging/discharging operation. On the other hand, the switching-type power supply is suitable for variable current control operation and of less power loss. However, it is of large current ripple in the constant current operation which would degrade the magnetic field stability in HTS-MRI imaging operation. The availability of the power supply system was discussed in MRI imaging of a mouse using an experimental HTS-MRI system. HTS-MRI imaging of mouse (~50 mm).
Superintegrable quantum mechanical systems with position dependent masses invariant with respect to two parametric Lie groups
Authors: Nikitin A G
Published: August 2023

Quantum mechanical systems with position dependent masses (PDMs) admitting two parametric Lie symmetry groups are classified. Namely, all PDM systems are specified which, in addition to their invariance w.r.t. a two parametric Lie group, admit at least one second order integral of motion. The presented classification is partially extended to the more generic systems which do not accept any Lie group.
Nonautonomous dynamics of local and nonlocal Fokas–Lenells models
Authors: Silem Abdselam , Lin Ji , Akhtar Naeem
Published: August 2023

We investigate the dynamics of solutions to the local and nonlocal nonautonomous Fokas–Lenells (FL) models. Solutions to the local and nonlocal reductions are presented using the Wronskian technique by imposing constraints on the double Wronskian solutions to the unreduced nonautonomous FL system. Classifications of the soliton solutions are shown in relation to the distribution of the eigenvalues. Moreover, dynamics of these solutions are presented, along with the impacts of the variable coefficient

α
(
t
)

. Notably, the coefficient

α
(
t
)

influences the top traces and velocities of the found solutions in both the local and nonlocal cases, enriching this study.
Highly reproducible and cost-effective one-pot organoid differentiation using a novel platform based on PF-127 triggered spheroid assembly
Authors: Zhang Xiao-Shan , Xie Gang , Ma Honghao , Ding Shuangjin , Wu Yi-Xia , Fei Yuan , Cheng Qiang , Huang Yanyi , Wang Yangming
Published: August 2023

Organoid technology offers sophisticated in vitro human models for basic research and drug development. However, low batch-to-batch reproducibility and high cost due to laborious procedures and materials prevent organoid culture standardization for automation and high-throughput applications. Here, using a novel platform based on the findings that Pluronic F-127 (PF-127) could trigger highly uniform spheroid assembly through a mechanism different from plate coating, we develop a one-pot organoid differentiation strategy. Using our strategy, we successfully generate cortical, nephron, hepatic, and lung organoids with improved reproducibility compared to previous methods while reducing the original costs by 80%–95%. In addition, we adapt our platform to microfluidic chips allowing automated culture. We showcase that our platform can be applied to tissue-specific screening, such as drug toxicity and transfection reagents testing. Finally, we generate NEAT1 knockout tissue-specific organoids and show NEAT1 modulates multiple signaling pathways fine-tuning the differentiation of nephron and hepatic organoids and suppresses immune responses in cortical organoids. In summary, our strategy provides a powerful platform for advancing organoid research and studying human development and diseases.
What Is the Current Best Drug Treatment for Hypertensive Heart Failure With Preserved Ejection Fraction? Review of the Totality of Evidence
Authors: Sevre Kaja , Rist Aurora , Wachtell Kristian , Devereux Richard B , Aurigemma Gerard P , Smiseth Otto A , Kjeldsen Sverre E , Julius Stevo , Pitt Bertram , Burnier Michel , Kreutz Reinhold , Oparil Suzanne , Mancia Giuseppe , Zannad Faiez
Published: August 2023

BACKGROUND

More than 90% of patients developing heart failure (HF) have an epidemiological background of hypertension. The most frequent concomitant conditions are type 2 diabetes mellitus, obesity, atrial fibrillation, and coronary disease, all disorders/diseases closely related to hypertension.

METHODS

HF outcome research focuses on decreasing mortality and preventing hospitalization for worsening HF syndrome. All drugs that decrease these HF endpoints lower blood pressure. Current drug treatments for HF are (i) angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin receptor neprilysin inhibitors, (ii) selected beta-blockers, (iii) steroidal and nonsteroidal mineralocorticoid receptor antagonists, and (iv) sodium-glucose cotransporter 2 inhibitors.

RESULTS

For various reasons, these drug treatments were first studied in HF patients with a reduced ejection fraction (HFrEF). However, subsequently, they have been investigated and, as we see it, documented as beneficial in HF patients with a preserved left ventricular ejection fraction (LVEF, HFpEF) and mostly hypertensive etiology, with effect estimates assessed partly on top of background treatment with the drugs already proven effective in HFrEF. Additionally, diuretics are given on symptomatic indications.

CONCLUSIONS

Considering the totality of evidence and the overall need for antihypertensive treatment and/or treatment of hypertensive complications in almost all HF patients, the principal drug treatment of HF appears to be the same regardless of LVEF. Rather than LVEF-guided treatment of HF, treatment of HF should be directed by symptoms (related to the level of fluid retention), signs (tachycardia), severity (NYHA functional class), and concomitant diseases and conditions. All HF patients should be given all the drug classes mentioned above if well tolerated.
A workflow to study mechanistic indicators for driver gene prediction with Moonlight
Authors: Nourbakhsh Mona , Saksager Astrid , Tom Nikola , Chen Xi Steven , Colaprico Antonio , Olsen Catharina , Tiberti Matteo , Papaleo Elena
Published: August 2023

Prediction of driver genes (tumor suppressors and oncogenes) is an essential step in understanding cancer development and discovering potential novel treatments. We recently proposed Moonlight as a bioinformatics framework to predict driver genes and analyze them in a system-biology-oriented manner based on -omics integration. Moonlight uses gene expression as a primary data source and combines it with patterns related to cancer hallmarks and regulatory networks to identify oncogenic mediators. Once the oncogenic mediators are identified, it is important to include extra levels of evidence, called mechanistic indicators, to identify driver genes and to link the observed gene expression changes to the underlying alteration that promotes them. Such a mechanistic indicator could be for example a mutation in the regulatory regions for the candidate gene. Here, we developed new functionalities and released Moonlight2 to provide the user with a mutation-based mechanistic indicator as a second layer of evidence. These functionalities analyze mutations in a cancer cohort to classify them into driver and passenger mutations. Those oncogenic mediators with at least one driver mutation are retained as the final set of driver genes. We applied Moonlight2 to the basal-like breast cancer subtype, lung adenocarcinoma and thyroid carcinoma using data from The Cancer Genome Atlas. For example, in basal-like breast cancer, we found four oncogenes (COPZ2, SF3B4, KRTCAP2 and POLR2J) and nine tumor suppressor genes (KIR2DL4, KIF26B, ARL15, ARHGAP25, EMCN, GMFG, TPK1, NR5A2 and TEK) containing a driver mutation in their promoter region, possibly explaining their deregulation. Moonlight2R is available at https://github.com/ELELAB/Moonlight2R.
Developmental regulation of the male urogenital papilla in the male marine teleost black rockfish, Sebastes schlegelii (Hilgendorf, 1880)
Authors: Wang Tao , Wang Xueying , Zhao Ning , Liu Qinghua , Song Zongcheng , Li Jun
Published: August 2023

The male external genitalia of the black rockfish (Sebastes schlegelii Hilgendorf, 1880) is a fleshy protrusion known as the urogenital papilla (UGP), which functions to deliver sperm into the female reproductive tract for internal fertilization. It is not known which genes regulate the development of the UGP. The aim of this study was to identify key genes that regulate the development of the UGP in black rockfish and to determine the distribution of androgen receptor gene (ar) in the UGP. A total of 26 adult males and 560 juvenile fish were used in the experiment, in which we divided all normally developing juveniles into normal development and androgen groups. We added methyltestosterone solution (100 μg/l) to the androgen group-treated fish tank, soaked for 2 h per day for 38 days, and sampled 5~10 samples each time every 5 days during the culture process. Gene expression changes related to UGP were analyzed with tissue specificity between control and androgen groups during sex differentiation, adult male maturation, and the copulation stage (September to December) using real-time quantitative polymerase chain reaction. The expression of ar was also localized by two-color in situ hybridization in the UGP region of juvenile fish. Androgen treatment enhanced ar expression levels and the ar signal was stronger in the UGP region of both adult breeding fish and androgen-treated juvenile fish. This study provides insights into the regulation of the external genitalia of black rockfish and presents vital information for the artificial breeding of viviparous fish.
Smoothened mediates medaka spermatogonia proliferation via Gli1–Rgcc–Cdk1 axis
Authors: Zhao Changle , Liu Xiang , Liu Lei , Li Jianeng , Liu Xingyong , Tao Wenjing , Wang Deshou , Wei Jing
Published: August 2023

The proliferation of spermatogonia directly affects spermatogenesis and male fertility, but its underlying molecular mechanisms are poorly understood. In this study, Smoothened (Smo), the central transducer of Hedgehog signaling pathway, was characterized in medaka (Oryzias latipes), and its role and underlying mechanisms in the proliferation of spermatogonia were investigated. Smo was highly expressed in spermatogonia. In ex vivo testicular organ culture and a spermatogonial cell line (SG3) derived from medaka mature testis, Smo activation promoted spermatogonia proliferation, while its inhibition induced apoptosis. The expression of glioma-associated oncogene homolog 1 (gli1) and regulator of cell cycle (rgcc) was significantly upregulated in SG3 after Smo activation. Furthermore, Gli1 transcriptionally upregulated the expression of rgcc, and Rgcc overexpression rescued cell apoptosis caused by Smo or Gli1 inhibition. Co-immunoprecipitation assay indicated that Rgcc could interact with cyclin-dependent kinase 1 (Cdk1) to regulate the cell cycle of spermatogonia. Collectively, our study firstly reveals that Smo mediates the proliferation of spermatogonia through Gli1–Rgcc–Cdk1 axis. In addition, Smo and Gli1 are necessary of the survival of spermatogonia. This study deepens our understanding of spermatogonia proliferation and survival at the molecular level, and provides insights into male fertility control and reproductive disease treatment.
Exposure to a phthalate mixture disrupts ovulatory progesterone receptor signaling in human granulosa cells in vitro
Authors: Hannon Patrick R , Akin James W , Curry Jr Thomas E
Published: August 2023

Exposure to phthalates disrupts ovarian function. However, limited studies have investigated the effects of phthalate mixtures on ovulation, especially in women. Human granulosa cells were used to test the hypothesis that exposure to a phthalate mixture (PHTmix) disrupts progesterone (P4)/progesterone receptor (PGR) signaling, which is a crucial pathway for ovulation. In addition, progestin and cyclic adenosine 3′, 5′-monophosphate (cAMP) supplementation were tested as methods to circumvent phthalate toxicity. Granulosa cells from women undergoing in vitro fertilization were acclimated in culture to regain responsiveness to human chorionic gonadotropin (hCG; clinical luteinizing hormone analogue). Granulosa cells were treated with or without hCG, and with or without PHTmix (1–500 μg/ml; dimethylsulfoxide = vehicle control) for 0.5–36 h. In the supplementation experiments, cells were treated with or without R5020 (stable progestin), and with or without 8-Br-cAMP (stable cAMP analogue). Exposure to hCG + PHTmix decreased P4 levels and mRNA levels of steroidogenic factors when compared to hCG. This was accompanied by decreased mRNA levels of PGR and downstream P4/PGR ovulatory mediators (ADAM metallopeptidase with thrombospondin type 1 motif 1 (ADAMTS1), C-X-C motif chemokine receptor 4 (CXCR4), pentraxin 3 (PTX3), and regulator of G protein signaling 2 (RGS2)) in the hCG + PHTmix groups compared to hCG. Exposure to hCG + PHTmix 500 μg/ml decreased cAMP levels and protein kinase A activity compared to hCG. Supplementation with progestin in the hCG + PHTmix 500 μg/ml group did not rescue toxicity, while supplementation with cAMP restored PGR levels and downstream P4/PGR mediator levels to hCG levels. These findings suggest that phthalate mixture exposure inhibits P4/PGR signaling in human granulosa cells via decreased steroidogenesis, cAMP levels, and protein kinase A activity. Restored P4/PGR signaling with cAMP supplementation provides a potential cellular target for intervention of phthalate-induced ovulatory dysfunction in women.
Paxillin knockout in mouse granulosa cells increases fecundity
Authors: Vann Kenji , Weidner Adelaide E , Walczyk Ariana C , Astapova Olga
Published: August 2023

Paxillin is an intracellular adaptor protein involved in focal adhesions, cell response to stress, steroid signaling, and apoptosis in reproductive tissues. To investigate the role of paxillin in granulosa cells, we created a granulosa-specific paxillin knockout mouse model using Cre recombinase driven by the Anti-Müllerian hormone receptor 2 gene promoter. Female granulosa-specific paxillin knockout mice demonstrated increased fertility in later reproductive age, resulting in higher number of offspring when bred continuously up to 26 weeks of age. This was not due to increased numbers of estrous cycles, ovulated oocytes per cycle, or pups per litter, but this was due to shorter time to pregnancy and increased number of litters in the granulosa-specific paxillin knockout mice. The number of ovarian follicles was not significantly affected by the knockout at 30 weeks of age. Granulosa-specific paxillin knockout mice had slightly altered estrous cycles but no difference in circulating reproductive hormone levels. Knockout of paxillin using clustered regularly interspaced short palindromic repeat-associated protein 9 (CRISPR-Cas9) in human granulosa-derived immortalized KGN cells did not affect cell proliferation or migration. However, in cultured primary mouse granulosa cells, paxillin knockout reduced cell death under basal culture conditions. We conclude that paxillin knockout in granulosa cells increases female fecundity in older reproductive age mice, possibly by reducing granulosa cell death. This study implicates paxillin and its signaling network as potential granulosa cell targets in the management of age-related subfertility.
Evolutionary fire ecology: An historical account and future directions
Authors: Pausas Juli G , Keeley Jon E
Published: August 2023

The idea that fire acts as an evolutionary force contributing to shaping species traits started a century ago, but had not been widely recognized until very recently. Among the first to realize this force were Edward B. Poulton, R. Dale Guthrie, and Edwin V. Komarek in animals and Willis L. Jepson, Walter W. Hough, Tom M. Harris, Philip V. Wells, and Robert W. Mutch in plants. They were all ahead of their time in their evolutionary thinking. Since then, evolutionary fire ecology has percolated very slowly into the mainstream ecology and evolutionary biology; in fact, this topic is still seldom mentioned in textbooks of ecology or evolution. Currently, there is plenty of evidence suggesting that we cannot understand the biodiversity of our planet without considering the key evolutionary role of fire. But there is still research to be done in order to fully understand fire's contribution to species evolution and to predicting species responses to rapid global changes.
A dietary polyphenol metabolite alters CA1 excitability ex vivo and mildly affects cortico-hippocampal field potential generators in anesthetized animals
Authors: Montero-Atalaya Marta , Expósito Sara , Muñoz-Arnaiz Ricardo , Makarova Julia , Bartolomé Begoña , Martín Eduardo , Moreno-Arribas María Victoria , Herreras Oscar
Published: August 2023

Dietary polyphenols have beneficial effects in situations of impaired cognition in acute models of neurodegeneration. The possibility that they may have a direct effect on the electrical activity of neuronal populations has not been tested. We explored the electrophysiological action of protocatechuic acid (PCA) on CA1 pyramidal cells ex vivo and network activity in anesthetized female rats using pathway-specific field potential (FP) generators obtained from laminar FPs in cortex and hippocampus. Whole-cell recordings from CA1 pyramidal cells revealed increased synaptic potentials, particularly in response to basal dendritic excitation, while the associated evoked firing was significantly reduced. This counterintuitive result was attributed to a marked increase of the rheobase and voltage threshold, indicating a decreased ability to generate spikes in response to depolarizing current. Systemic administration of PCA only slightly altered the ongoing activity of some FP generators, although it produced a striking disengagement of infraslow activities between the cortex and hippocampus on a scale of minutes. To our knowledge, this is the first report showing the direct action of a dietary polyphenol on electrical activity, performing neuromodulatory roles at both the cellular and network levels.
Using the AQbD Approach, Development and Validation of a Simple, Rapid Stability Indicating Chromatographic Method for Quantification of Related Impurities of Apixaban
Authors: Kilari Jayasri , Brahman Pradeep Kumar
Published: August 2023

Apixaban is a new oral anticoagulant that has been approved by the United States Food and Drug Administration for the prevention of stroke and other cardiovascular complications in people with non-valvular atrial fibrillation. Then, later, it was given the green light to treat deep venous thrombosis and pulmonary embolism. The biggest challenge in the development of pharmaceutical drugs is comprehending science- and risk-based techniques for developing and maintaining analytical procedures appropriate for evaluating the quality of drug substances and drug products. The improved technique provides a methodical strategy to acquire and improve understanding of an analytical method. The current study discusses the related substances method development for an apixaban drug substance employing a regulated authority refined and approved approach of the quality-by-design concept. For the quantification of impurities, and apixaban drug substance, a simple, quick and stability-indicating reverse-phase liquid chromatographic method was developed using a full factorial design. The separation between apixaban and its nine impurities was accomplished using an Zorbax Stable Bond Phenyl, 150 × 4.6 mm, 5 μm column. The mobile-phase components for gradient elution at a flow rate of 1.2 mL/min were chosen to be a mixture of water, acetonitrile, methanol and perchloric acid in various ratios with a total run time of 15 min. Chromatograms were extracted at 278 nm after a 5 μL solution injection. According to regulatory requirements, the developed method has been validated for its intended purpose.
Remdesivir Reduced Mortality in Immunocompromised Patients Hospitalized for COVID-19 Across Variant Waves: Findings From Routine Clinical Practice
Authors: Mozaffari Essy , Chandak Aastha , Gottlieb Robert L , Chima-Melton Chidinma , Read Stephanie H , Jiang Heng , Chiang Mel , Lee EunYoung , Gupta Rikisha , Berry Mark , Kalil Andre C
Published: August 2023

Background

Immunocompromised patients are at high risk of severe coronavirus disease 2019 (COVID-19) and death, yet treatment strategies for immunocompromised patients hospitalized for COVID-19 reflect variations in clinical practice. In this comparative effectiveness study, we investigated the effect of remdesivir treatment on inpatient mortality among immunocompromised patients hospitalized for COVID-19 across all variants of concern (VOC) periods.

Methods

Data for immunocompromised patients hospitalized for COVID-19 between December 2020 and April 2022 were extracted from the US PINC AITM Healthcare Database. Patients who received remdesivir within 2 days of hospitalization were matched 1:1 using propensity score matching to patients who did not receive remdesivir. Additional matching criteria included admission month, age group, and hospital. Cox proportional hazards models were used to examine the effect of remdesivir on risk of 14- and 28-day mortality during VOC periods.

Results

A total of 19 184 remdesivir patients were matched to 11 213 non-remdesivir patients. Overall, 11.1% and 17.7% of remdesivir patients died within 14 and 28 days, respectively, compared with 15.4% and 22.4% of non-remdesivir patients. Remdesivir was associated with a reduction in mortality at 14 (hazard ratio [HR], 0.70; 95% confidence interval, .62–.78) and 28 days (HR, 0.75; 95% CI, .68–.83). The survival benefit remained significant during the pre-Delta, Delta, and Omicron periods.

Conclusions

Prompt initiation of remdesivir in immunocompromised patients hospitalized for COVID-19 is associated with significant survival benefit across all variant waves. These findings provide much-needed evidence relating to the effectiveness of a foundational treatment for hospitalized COVID-19 patients among a high-risk population.
Truncated Differential Attacks On Symmetric Primitives With Linear Key Schedule: WARP And Orthros
Authors: Hou Shiqi , Wu Baofeng , Wang Shichang , Guo Hao , Lin Dongdai
Published: August 2023

In truncated differential cryptanalysis of symmetric primitives, a generalized framework is to search a distinguisher concerning part of output differences, like truncated differential distribution (TDD) on certain bits (e.g. a nibble) first, and then append several rounds before and after it to recover the secret key. The logarithmic likelihood ratio statistic with respect to the TDD is usually used to distinguish guessed key bits. In this paper, we study how to improve the effect of truncated differential cryptanalysis by considering key schedules of the attacked ciphers. It turns out that for a cipher with a simple key schedule, certain guessed subkey bits may reveal information of the master key, which will help build a stronger TDD distinguisher and reduce the key recovery complexity or attack more rounds. As a result, we explore heuristic techniques to search key-recovery-friendly TDDs and construct automatic search models based on MILP. The refined methods are applied to two recent designs of symmetric primitives, WARP and Orthros, together with peculiarities of their structures as well. For WARP, after making two observations on relations between certain differences with key bits, we propose an algorithm that can find TDDs with low complexities and having potentialities to cover more rounds. Consequently, we launch key recovery attacks on 24 to 27 rounds of WARP. When it comes to Orthros, we present a two-step search algorithm to balance the number of guessed key bits and TDDs, obtaining a key recovery attack on a 7-round variant of it in the weak-key setting. Finally, we perform several verification experiments on round-reduced versions of WARP and Orthros, and the experimental results are consistent with the theoretical distributions and the analysis of generalized key recovery attack framework.
Biomedical relation extraction with knowledge base–refined weak supervision
Authors: Yoon Wonjin , Yi Sean , Jackson Richard , Kim Hyunjae , Kim Sunkyu , Kang Jaewoo
Published: August 2023

Biomedical relation extraction (BioRE) is the task of automatically extracting and classifying relations between two biomedical entities in biomedical literature. Recent advances in BioRE research have largely been powered by supervised learning and large language models (LLMs). However, training of LLMs for BioRE with supervised learning requires human-annotated data, and the annotation process often accompanies challenging and expensive work. As a result, the quantity and coverage of annotated data are limiting factors for BioRE systems. In this paper, we present our system for the BioCreative VII challenge—DrugProt track, a BioRE system that leverages a language model structure and weak supervision. Our system is trained on weakly labelled data and then fine-tuned using human-labelled data. To create the weakly labelled dataset, we combined two approaches. First, we trained a model on the original dataset to predict labels on external literature, which will become a model-labelled dataset. Then, we refined the model-labelled dataset using an external knowledge base. Based on our experiment, our approach using refined weak supervision showed significant performance gain over the model trained using standard human-labelled datasets. Our final model showed outstanding performance at the BioCreative VII challenge, achieving 3rd place (this paper focuses on our participating system in the BioCreative VII challenge).

Database URL: http://wonjin.info/biore-yoon-et-al-2022
Incidence, risk factors, and outcomes of atrial functional mitral regurgitation in patients with atrial fibrillation or sinus rhythm
Authors: Naser Jwan A , Michelena Hector I , Lin Grace , Scott Christopher G , Lee Eunjung , Kennedy Austin M , Noseworthy Peter A , Pellikka Patricia A , Nkomo Vuyisile T , Pislaru Sorin V
Published: August 2023

Aims

Atrial functional mitral regurgitation (AFMR) has been associated with atrial fibrillation (AF) and heart failure with preserved ejection fraction. However, data on incident AFMR are scarce. We aimed to study the incidence, risk factors, and clinical significance of AFMR in AF or sinus rhythm (SR).

Methods and results

Adults with new diagnosis of AF and adults in SR were identified. Patients with >mild MR at baseline, primary mitral disease, cardiomyopathy, left-sided valve disease, previous cardiac surgery, or with no follow-up echocardiogram were excluded. Diastolic dysfunction (DD) was indicated by ≥2/4 abnormal diastolic function parameters [mitral medial e′, mitral medial E/e′, tricuspid regurgitation velocity, left atrial volume index (LAVI)]. Overall, 1747 patients with AF and 29 623 in SR were included. Incidence rate of >mild AFMR was 2.6 per 100 person-year in new-onset AF and 0.7 per 100 person-year in SR, P < 0.001. AF remained associated with AFMR in a propensity score-matched analysis based on age, sex, and comorbidities between AF and SR [hazard ratio: 3.80 (95% confidence interval 3.04–4.76)]. Independent risk factors associated with incident AFMR were age ≥65 years, female sex, LAVI, and DD in both AF and SR, in addition to rate (vs. rhythm) control in AF. Incident AFMR was independently associated with all-cause death in both groups (both P < 0.001).

Conclusions

AF conferred a three-fold increase in the risk of incident AFMR. DD, older age, left atrial size, and female sex were independent risk factors in both SR and AF, while rhythm control was protective. AFMR was universally associated with worse mortality.
Skeletal and dental maxillary morphological characteristics in patients with impacted canines: systematic review and meta-analysis
Authors: Gudelevičiūtė Ieva , Spaičytė Nerija , Smailienė Dalia
Published: August 2023

Background

There are a few hypotheses for the origin of palatally impacted canines (PIC). Nevertheless, the results of different studies are controversial.

Objective

Considering the evidence available in the literature to determine the skeletal and dentoalveolar dimensions in patients with PIC using cone beam computed tomography (CBCT).

Search methods

This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement. The literature search with no publication date restriction in five databases and hand searching was performed until April 2023.

Data collection and analysis

Data assessing the skeletal and dentoalveolar characteristics of subjects with PIC evaluated with CBCT was extracted, and the studies’ quality was evaluated with the Newcastle-Ottawa Scale (NOS). Skeletal and dentoalveolar characteristics of subjects with PIC were compared with non-impacted subjects or non-impacted sides. MedCalc software was used to perform the meta-analysis. Statistical heterogeneity was assessed using the chi-square and I-square tests.

Results

The initial database search identified a total of 1153 studies. After applying the selection criteria, nine articles were included in the systematic review and meta-analysis. According to the NOS, all included articles were graded as “Good” quality. The meta-analysis showed a non-significant difference in measuring dentoalveolar height, alveolar first molar width, and basal lateral width. Controversial results were observed when evaluating both basal and alveolar first premolar widths. A significant difference was found when assessing anterior alveolar crest height and basal maxillary width.

Conclusions

Studies demonstrated the reduction of both dentoalveolar and skeletal maxillary parameters of the patients with PIC. The meta-analysis indicated that PIC correlates to both vertical and transverse skeletal dimensions of the maxilla. However, the results remain controversial. The findings should be interpreted with caution due to different study designs and unbalanced groups in the included studies; therefore, further research is needed for more reliable conclusions.

Registration

This systematic review and meta-analysis were registered in the International Prospective Register of Systematic Reviews (PROSPERO CRD42022362124)