bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiphysics simulation of VVER-1200 fuel performance during normal operating conditions
Authors: Yassin Khaled M. , Hassan Mohamed H. , Ghoneim Mohammad M. , Elkolil Mostafa S. , Alyan Adel , Agamy Said A.
Published: February 2023

Nuclear fuel performance modeling and simulation are critical tasks for nuclear fuel design optimization and safety analysis under normal and transient conditions. Fuel performance is a complicated phenomenon that involves thermal, mechanical, and irradiation mechanisms and requires special multiphysics modules. In this study, a fuel performance model was developed using the COMSOL Multiphysics platform. The modeling was performed for a 2D axis-symmetric geometry of a UO2 fuel pellet in the E110 clad for VVER-1200 fuel. The modeling considers all relevant phenomena, including heat generation and conduction, gap heat transfer, elastic strain, mechanical contact, thermal expansion, grain growth, densification, fission gas generation and release, fission product swelling, gap/plenum pressure, and cladding thermal and irradiation creep. The model was validated using a code-to-code evaluation of the fuel pellet centerline and surface temperatures in the case of constant power, in addition to validation of fission gas release (FGR) predictions. This prediction proved that the model could perform according to previously published VVER nuclear fuel performance parameters. A sensitivity study was also conducted to assess the effects of uncertainty on some of the model parameters. The model was then used to predict the VVER-1200 fuel performance parameters as a function of burnup, including the temperature profiles, gap width, fission gas release, and plenum pressure. A compilation of related material and thermomechanical models was conducted and included in the modeling to allow the user to investigate different material/performance models. Although the model was developed for normal operating conditions, it can be modified to include off-normal operating conditions.
Grey Relational Analysis–Based MADM Strategy Under Possibility Environment and Its Application in the Identification of Most Important Parameter Affecting Climate Change and the Impact of Urbanization on Hydropower Plants
Authors: Shil Bimal , Sinha Prasenjit , Das Suman , Tripathy Binod Chandra , Poojary Prasanna
Published: February 2023

This paper aims to establish the notion of Hamming distance under the possible environment and propose a multi-attribute decision-making (MADM) strategy based on grey relational analysis (GRA) under the Possibility environment. This study identified the most critical parameter or factors affected by climate change, urbanization, and machine failures. Furthermore, we validate the proposed MADM strategy by solving a real-world numerical example, namely, “identification of the most important parameters affecting climate change and the impact of urbanization on hydropower plants.”
Determination of the Temperature-Dependent Resonance Behavior of Ultrasonic Transducers Using the Finite-Element Method
Authors: Wellendorf Axel , von Damnitz Lukas , Nuri Abdul Wahab , Anders Denis , Trampnau Sebastian
Published: February 2023

Purpose

Langevin transducers are ultrasonic transducers that convert electrical into mechanical energy through the piezoelectric effect. This class of transducers achieves the highest efficiency in their mechanical resonance. Studies have shown that the resonant frequency changes with temperature. The aim of this contribution is to reproduce this temperature-dependence resonance frequency as accurately as possible with FEM simulations.

Methods

Therefore, the temperature-dependent resonance behavior of Langevin transducers is examined experimentally. A FEM model is created on the basis of temperature-dependent measured material coefficients. Using parameter correlations and optimization algorithms, the FEM model is fitted and validated by experimental results. Six variants of Langevin transducers are examined in the range from 30 °C to 80 °C with resonance frequencies between 34 and 38 kHz. They differ in three geometries and two materials.

Results

The experimental results show that the resonance frequencies decrease with increasing temperatures by 5.0–19.4 Hz/°C, depending on the material and geometry. As decisive parameters for the model fitting of the FEM results, three function-dependent stiffness coefficients of the piezoelectric material PZT8 and the Young’s moduli of the metallic materials are determined by parameter correlation.

Conclusion

Through the targeted fitting of these function-dependent parameters, the calculation of the resonance frequencies of Langevin transducers can be qualitatively and quantitatively improved, independent of shape and material.
Effect of thermoplastic impregnation on the mechanical behaviour of textile reinforcement for concrete
Authors: Heins Kira , Lesker Sophie , Pütz Julius , Hüntemann Michael , Gries Thomas
Published: February 2023

In recent decades, textile reinforced concrete (TRC) has become increasingly important, both in research and the construction industry. It is a resource-efficient material alternative to conventional, steel reinforced concrete due to the use of non-corroding high-performance textile reinforcements and the resulting material savings. Typically, thermoset polymer materials are used as impregnation for the textile reinforcement to improve the mechanical behaviour. However, due to their chemically crosslinking behaviour, these materials prevent subsequent product-specific shaping of the reinforcement. The use of thermoplastic impregnation materials shows potential to allow shaping by utilizing the thermal forming behaviour, provided that the resulting properties of the reinforcement system in terms of mechanical performance are not inferior to those of the already available impregnations. In this study, four impregnation systems are investigated on AR-glass textiles with regard to their effect on the mechanical behaviour of the reinforcement and classified in comparison to the current benchmark epoxy and styrene butadiene rubber (SBR) by conducting single yarn tensile tests and supporting microscopy analysis. The thermoplastic impregnation increased the tensile strength of the AR glass fibre to values in the range of around 1200 MPa with a low coating content to 1500 MPa with a high coating content. A strong dependence of the impregnation efficiency on the impregnation composition, in this case the solid content of the dispersion, was demonstrated as a result of pore formation. In conclusion, thermoplastic impregnation materials achieve strengths comparable to those of commonly used materials.
The role of entrepreneurship policy and culture in transitional routes from entrepreneurial intention to job creation: a moderated mediation model
Authors: Qin Shuai , Chen Xiaolan
Published: February 2023

It has long been assumed that entrepreneurship has significant social and economic benefits, including the creation of jobs. Based on the literature, however, small businesses have often had difficulty expanding to recruit and even surviving due to their plight. In spite of this, little is known about how institutional factors facilitate and constrain the path from entrepreneurial intention to create jobs. Therefore, we develop and test a moderated mediation model to examine how the government's policymaking and national entrepreneurship culture regulate entrepreneurship-based job creation. With the Adult population survey and the National expert survey of the Global Entrepreneurship Monitor (GEM), this study compiled 417 observations from 39 European and North American countries between 2002 and 2020. We prove the partial mediation effect of entrepreneurial behaviour on the relationship between individuals' entrepreneurial intention and job creation. The findings of our study suggest that institutional changes should be mobilised to relieve the pressures on small business owners instead of residing on size-neutral approaches. Furthermore, a progressive, contextually based entrepreneurial culture serves as a critical stimulant to the growth of latent entrepreneurs and early-stage start-ups. Therefore, the study not only describes a new path that underpins entrepreneurship-based job creation, but also highlights a new motive for necessary institutional change.
RETRACTED ARTICLE: How Have the COVID-19 Pandemic and Market Sentiment Affected the FX Market? Evidence from Statistical Models and Deep Learning Algorithms
Authors: Luo Hang , Luo Xiaoyu , Gu Shuhao
Published: February 2023

This paper attempts to investigate the impact of the COVID-19 pandemic and market sentiment on the dynamics of USD/JPY, GBP/USD, and USD/CNY. We compose the market sentiment variable and incorporate the newly confirmed COVID-19 cases and sentiment variable into the traditional exchange rate forecasting model. We find that confirmed COVID-19 cases and sentiment variables in the US, Japan, UK, and China in the period of January 23rd, 2020 to September 14th, 2021 are significant in explaining the bilateral exchange rate movement. Recurrent neural network (RNN) and long short-term memory (LSTM) models outperform the other deep learning models and vector autoregressive (VAR) model in forecasting the bilateral exchange rate movement during the COVID-19 pandemic period. Further analysis using high-frequency intraday data and ensemble models shows that ensemble models significantly improve the accuracy of exchange rate prediction, as they are better at coping with the nonlinear and nonstationary features of exchange rate time series.
Effects of High Temperature on COVID‐19 Deaths in U.S. Counties
Authors: Chu Bowen , Chen Renjie , Liu Qi , Wang Haikun
Published: February 2023

The United States of America (USA) was afflicted by extreme heat in the summer of 2021 and some states experienced a record‐hot or top‐10 hottest summer. Meanwhile, the United States was also one of the countries impacted most by the coronavirus disease 2019 (COVID‐19) pandemic. Growing numbers of studies have revealed that meteorological factors such as temperature may influence the number of confirmed COVID‐19 cases and deaths. However, the associations between temperature and COVID‐19 severity differ in various study areas and periods, especially in periods of high temperatures. Here we choose 119 US counties with large counts of COVID‐19 deaths during the summer of 2021 to examine the relationship between COVID‐19 deaths and temperature by applying a two‐stage epidemiological analytical approach. We also calculate the years of life lost (YLL) owing to COVID‐19 and the corresponding values attributable to high temperature exposure. The daily mean temperature is approximately positively correlated with COVID‐19 deaths nationwide, with a relative risk of 1.108 (95% confidence interval: 1.046, 1.173) in the 90th percentile of the mean temperature distribution compared with the median temperature. In addition, 0.02 YLL per COVID‐19 death attributable to high temperature are estimated at the national level, and distinct spatial variability from −0.10 to 0.08 years is observed in different states. Our results provide new evidence on the relationship between high temperature and COVID‐19 deaths, which might help us to understand the underlying modulation of the COVID‐19 pandemic by meteorological variables and to develop epidemic policy response strategies.
Has There Been a Recent Shallowing of Tropical Cyclones?
Authors: Lai Tsz‐Kin , Toumi Ralf
Published: February 2023

Many aspects of tropical cyclone (TC) properties at the surface have been changing but any systematic vertical changes are unknown. Here, we document a recent trend of high thick clouds of TCs. The global inner‐core high thick cloud fraction measured by satellite has decreased from 2002 to 2021 by about 10% per decade. The TC inner‐core surface rain rate is also found to have decreased during the same period by a similar percentage. This suppression of high thick clouds and rain has been largest during the intensification phase of the strongest TCs. Hence, these two independent and consistent observations suggest that the TC inner‐core convection has weakened and that TCs have become shallower recently at least. For this period, the lifetime maximum intensity of major TCs has not changed and this suggests an increased efficiency of the spin‐up of TCs.
Electron Energization by Inertial Alfvén Waves in Density Depleted Flux Tubes at Jupiter
Authors: Damiano P. A. , Delamere P. A. , Kim E.‐H. , Johnson J. R. , Ng C. S.
Published: February 2023

Juno satellite observations have illustrated substantial examples of broadband electron energization up to 105–106 eV levels. In order to explain these observations, we use a hybrid gyrofluid kinetic‐electron model in an untilted dipolar topology to illustrate energization to high levels in weak current conditions by inertial Alfvén waves close to the Jupiter ionosphere for ambient plasma densities and magnetic field perturbations inferred from Juno satellite observations. The key to the high energization is the extremely low densities evident in the observations which necessitates the acceleration of electrons to very high velocities in order to carry the field‐aligned current.
Iceland Kinematics From InSAR
Authors: Cao Yunmeng , Jónsson Sigurjón , Hreinsdóttir Sigrún
Published: February 2023

Large‐scale ground deformation in Iceland is dominated by extensional plate‐boundary deformation, where the Mid‐Atlantic Ridge crosses the island, and by uplift due to glacial isostatic adjustment (GIA) from thinning and retreat of glaciers. While this deformation is mostly steady over multiple years, it is modulated by smaller‐scale transient deformation associated with, for example, earthquakes, volcanic unrest, and geothermal exploitation. Here, we combine countrywide Sentinel‐1 interferometric synthetic aperture radar (InSAR) data (from six tracks) from 2015 to 2021 with continuous Global Navigation Satellite System observations to produce time series of displacements across Iceland. The InSAR results were improved in a two‐step tropospheric mitigation procedure, using (a) global atmospheric models to reduce long‐wavelength and topography‐correlated tropospheric signals, and (b) modeling of the stochastic properties of the residual troposphere. Our results significantly improve upon earlier countrywide InSAR results, which were based on InSAR stacking, as we use more data, better data weighting, and advanced InSAR corrections to produce time series of ground displacements instead of just velocities. We fuse the three ascending and three descending track results to estimate maps of East and Up velocities, which clearly show the large‐scale extension and GIA deformation. Using revised plate‐spreading and GIA models, based on these new ground velocity maps, we remove the large‐scale and steady deformation from the InSAR time series and analyze the remaining transient deformations. Our results demonstrate the importance of (a) mitigating InSAR tropospheric signals over Iceland and of (b) solving for time series of deformation, not just velocities, as multiple transient deformation processes are present.
Water Recycling in the Deep Earth: Insights From Integrated μ‐XRF, THz‐TDS Spectroscopy, TG, and DCS of High‐Pressure Granulite
Authors: Li Shan‐Shan , Qiu Kun‐Feng , Hernández‐Uribe David , Gao Yi‐Xue , Santosh M. , Huang Hao‐Chong , Zheng Zhi‐Yuan , Zhang Zi‐Li , Gao Shi‐Chen
Published: February 2023

Subduction‐related dehydration and exhumation‐related rehydration play an important role in water recycling on Earth. Water can be transported to the deep mantle through crustal subduction, whereas the behavior of water in the subducted crust during exhumation remains enigmatic. Here, we use an integrated micro X‐ray fluorescence spectrometry, transmission terahertz time‐domain, thermogravimetry, and differential scanning calorimetry approach for the first time on high‐pressure mafic granulite and amphibolite to investigate the water species and contents, as well as exhumation rehydration reactions. Our study demonstrates that garnet, hornblende, and ilmenite contain considerable amounts, and plagioclase contains minor amounts of water as molecular and structural species, whereas quartz contains only a minor amount of structural water. Water released from garnet and external fluids from the grain boundary will either migrate into hornblende, plagioclase, ilmenite, and quartz, or stored in the mantle wedge, or further subducted into the deep mantle. We suggest that water recycling between the Earth's surface and deep mantle is an unequilibrium process, and the lower crust and mantle may store a significant amount of water in deep Earth and can function as a container to feed and maintain the water recycling balance.
Soil Moisture and Atmospheric Aridity Impact Spatio‐Temporal Changes in Evapotranspiration at a Global Scale
Authors: Zhang Wenmin , Koch Julian , Wei Fangli , Zeng Zhenzhong , Fang Zhongxiang , Fensholt Rasmus
Published: February 2023

Evapotranspiration (ET) constitutes the water exchange from land to the atmosphere, which in turn modulates precipitation and soil moisture (SM). Multiple lines of evidence document complex feedbacks between changes in ET and temperature, atmospheric CO2 and vegetation greening. However, the existing analyses on global changes in ET do not account for the direct effects of SM supply and atmospheric water demand, expressed by vapor pressure deficit (VPD), while considering multiple environmental variables. Here we evaluated the performance of ET products using 140 flux towers included in the FLUXNET database. All ET products show reasonable performance, with an overall correlation higher than 0.7 and better performance at a higher latitude. From analysis of the ensemble mean of annual ET, we show insignificant (P = 0.06) trends in global ET during 1982–2020 and a significantly (P < 0.01) increasing trend during 2002–2020. Changes in GLEAM ET generally exert a positive response to changes in SM and a negative response to changes in VPD. Yet, these effects are not globally consistent and are largely determined by changes in vegetation transpiration. Using our finding as a benchmark, Earth System Models mostly reproduce the positive response of ET to SM with less coupling strength, while showing negative effects of VPD on ET with stronger coupling strength. Our study highlights that concurrent soil drying and atmospheric aridity could intensify water exchanges and the importance of realistically representing SM‐VPD‐ET interactions in models for accurate predictions of the hydrological cycle.
Differential global distribution of marine picocyanobacteria gene clusters reveals distinct niche-related adaptive strategies
Authors: Doré Hugo , Guyet Ulysse , Leconte Jade , Farrant Gregory K , Alric Benjamin , Ratin Morgane , Ostrowski Martin , Ferrieux Mathilde , Brillet-Guéguen Loraine , Hoebeke Mark , Siltanen Jukka , Le Corguillé Gildas , Corre Erwan , Wincker Patrick , Scanlan David J , Eveillard Damien , Partensky Frédéric , Garczarek Laurence
Published: February 2023

The ever-increasing number of available microbial genomes and metagenomes provides new opportunities to investigate the links between niche partitioning and genome evolution in the ocean, especially for the abundant and ubiquitous marine picocyanobacteria Prochlorococcus and Synechococcus. Here, by combining metagenome analyses of the Tara Oceans dataset with comparative genomics, including phyletic patterns and genomic context of individual genes from 256 reference genomes, we show that picocyanobacterial communities thriving in different niches possess distinct gene repertoires. We also identify clusters of adjacent genes that display specific distribution patterns in the field (eCAGs) and are thus potentially involved in the same metabolic pathway and may have a key role in niche adaptation. Several eCAGs are likely involved in the uptake or incorporation of complex organic forms of nutrients, such as guanidine, cyanate, cyanide, pyrimidine, or phosphonates, which might be either directly used by cells, for example for the biosynthesis of proteins or DNA, or degraded to inorganic nitrogen and/or phosphorus forms. We also highlight the enrichment of eCAGs involved in polysaccharide capsule biosynthesis in Synechococcus populations thriving in both nitrogen- and phosphorus-depleted areas vs. low-iron (Fe) regions, suggesting that the complexes they encode may be too energy-consuming for picocyanobacteria thriving in the latter areas. In contrast, Prochlorococcus populations thriving in Fe-depleted areas specifically possess an alternative respiratory terminal oxidase, potentially involved in the reduction of Fe(III) to Fe(II). Altogether, this study provides insights into how phytoplankton communities populate oceanic ecosystems, which is relevant to understanding their capacity to respond to ongoing climate change.
Comorbidities in autism spectrum disorder and their etiologies
Authors: Khachadourian Vahe , Mahjani Behrang , Sandin Sven , Kolevzon Alexander , Buxbaum Joseph D. , Reichenberg Abraham , Janecka Magdalena
Published: February 2023

Individuals with autism spectrum disorder (ASD), in addition to the core features of the disease, experience a higher burden of co-occurring medical conditions. This study sought to describe the frequency and distribution of comorbidit conditions in individuals with ASD, and systematically evaluate the possibility that pre- and postnatal exposures (e.g., preterm birth, hypoxia at birth, traumatic brain injury, and fetal alcohol syndrome) associated with ASD may also be linked with distinct comorbidities. We used the SPARK study database, launched by the Simons Foundation Autism Research Initiative (SFARI). Comorbidities considered in the study included neurological, cognitive, psychiatric, and physical conditions. The study sample consisted of 42,569 individuals with ASD and their 11,389 non-ASD siblings (full and half siblings). Majority (74%) of individuals with ASD had at least one comorbidity, and had a greater average number of comorbidities than their non-ASD siblings. Preterm birth and hypoxia at birth were the most common peri-natal exposures in the sample. In logistic regression models adjusted for covariates, these exposures were associated with several distinct comorbidities in ASD cases, including attention and behavior problems, psychiatric and neurological disorders, and growth conditions. A similar pattern of association was also observed in non-ASD siblings. Our findings underscore that individuals with ASD experience a greater burden of comorbidities, which could be partly attributable to the higher rates of perinatal exposures compared to their non-ASD siblings. Study findings, if replicated in other samples, can inform the etiology of comorbidity in ASD.
Randomised controlled trial of breast cancer and multiple disease prevention weight loss programmes vs written advice amongst women attending a breast cancer family history clinic
Authors: Harvie Michelle , French David P. , Pegington Mary , Lombardelli Cheryl , Krizak Suzy , Sellers Katharine , Barrett Emma , Gareth Evans D. , Cutress Ramsey , Wilding RGN Andrea , Graves Lee , Howell Anthony
Published: February 2023

Background

Overweight and obesity are common amongst women attending breast cancer Family History, Risk and Prevention Clinics (FHRPCs). Overweight increases risk of breast cancer (BC) and conditions including1 cardiovascular disease (CVD) and type-2 diabetes (T2D). Clinics provide written health behaviour advice with is likely to have minimal effects. We assessed efficacy of two remotely delivered weight loss programmes vs. written advice.

Method

210 women with overweight or obesity attending three UK FHRPCs were randomised to either a BC prevention programme (BCPP) framed to reduce risk of BC (n = 86), a multiple disease prevention programme (MDPP) framed to reduce risk of BC, CVD and T2D (n = 87), or written advice (n = 37). Change in weight and health behaviours were assessed at 12-months.

Results

Weight loss at 12 months was −6.3% (−8.2, −4.5) in BCPP, −6.0% (−7.9, −4.2) in MDPP and −3.3% (−6.2, −0.5) in the written group (p = 0.451 across groups). The percentage losing ≥10% weight in these groups were respectively 34%, 23% and 14% (p = 0.038 across groups).

Discussion

BCPP and MDPP programmes resulted in more women achieving ≥10% weight loss, but no evidence of additional benefits of MDPP. A multicentre RCT to test the BCPP across UK FHRPCs is warranted.

Clinical Trial Registration ISRCTN16431108.
NRP1 promotes prostate cancer progression via modulating EGFR-dependent AKT pathway activation
Authors: Zhang Peng , Chen Liang , Zhou Fenfang , He Zhiwen , Wang Gang , Luo Yongwen
Published: February 2023

Prostate cancer (PCa) is the most common malignant tumor with a high global incidence in males. The mechanism underlying PCa progression is still not clear. This study observed that NRP1 was highly expressed in PCa and associated with poor prognosis in PCa patients. Functionally, NRP1 depletion attenuated the proliferation and migration ability of PCa cells in vitro and in vivo, while NRP1 overexpression promoted PCa cell proliferation and migration. Moreover, it was observed that NRP1 depletion induced G1 phase arrest in PCa cells. Mechanistically, HIF1α is bound to the specific promoter region of NRP1, thereby regulating its transcriptional activation. Subsequently, NRP1 interacted with EGFR, leading to EGFR phosphorylation. This study also provided evidence that the b1/b2 domain of NRP1 was responsible for the interaction with the extracellular domain of EGFR. Moreover, EGFR mediated NRP1-induced activation of the AKT signaling pathway, which promoted the malignant progression of PCa. In addition, the administration of NRP1 inhibitor EG01377 significantly inactivated the EGFR/AKT signaling axis, thereby suppressing PCa progression. In conclusion, the findings from this study highlighted the molecular mechanism underlying NRP1 expression in PCa and provide a potential predictor and therapeutic target for clinical prognosis and treatment of PCa.
MiR-130a-3p regulates FUNDC1-mediated mitophagy by targeting GJA1 in myocardial ischemia/reperfusion injury
Authors: Yan Yan , Tian Liu-yang , Jia Qian , Han Yang , Tian Yu , Chen Hui-ning , Cui Sai-jia , Xi Jie , Yao Yong-ming , Zhao Xiao-jing
Published: February 2023

Understanding the complex pathogenesis in myocardial ischemia/reperfusion (I/R) injury (IRI) is an urgent problem in clinical trials. Increasing pieces of evidence have suggested that miRNAs are involved in the occurrence and development of heart diseases by regulating mitochondria-related gene expression. Mitochondria have been acknowledged as the key triggers of cardiac I/R injury. However, the potential impact of miR-130a on mitochondria remains unclear in myocardial IRI. Exploring the regulatory mechanism of miR-130a on mitochondria may provide a new target for IRI therapy. In the present study, we found that miR-130a significantly increased in acute myocardial infarction (AMI) patients and myocardial I/R rats. MiR-130a could downregulate the viability of cardiomyocytes and the knockdown of miR-130a could protect the viability of cardiomyocytes under hypoxia-reoxygenation (HR). Over-expression of miR-130a resulted in mitochondrial dysfunction. It was evidenced by decreases in mitochondrial ATP production, mitochondrial membrane potential (MMP), and an increase in reactive oxygen species (ROS) production. However, suppression of miR-130a could protect against mitochondrial damage, show elevation of mitochondrial ATP production rate and MMP, and reduce ROS production. We further explored the effect of miR-130a on the mitochondrial quality control (QMC) system by determining mitochondrial-protein-specific proteases and analyzed mitochondrial morphology by fluorescence imaging and electron microscopy, respectively. It was noted that miR-130a could suppress mitochondrial fusion and FUNDC1-mediated mitophagy to accelerate myocardial IRI. Moreover, we investigated the potential miR-130a targeted mitochondria-related genes to understand the regulatory mechanism of miR-130a in the setting of myocardial IRI. It was revealed that miR-130a targeted GJA1, and GJA1 rescued IRI by enhancing ATP production rate and oxidative phosphorylation, meanwhile protecting cell viability, MMP, and activating mitophagy. In addition, the knockdown of miR-130a significantly activated FUNDC1-mediated mitophagy, while the knockdown of GJA1 reversed the relevant response. Collectively, our findings suggest that miR-130a regulates FUNDC1-mediated mitophagy by targeting GJA1 in myocardial IRI.
The mechanism of programmed death and endoplasmic reticulum stress in pulmonary hypertension
Authors: Sun Yang , Liu Shasha , Chen Chen , Yang Songwei , Pei Gang , Lin Meiyu , Wang Ting , Long Junpeng , Yan Qian , Yao Jiao , Lin Yuting , Yi Fan , Meng Lei , Tan Yong , Ai Qidi , Chen Naihong , Yang Yantao
Published: February 2023

Pulmonary hypertension (PH) was a cardiovascular disease with high morbidity and mortality. PH was a chronic disease with complicated pathogenesis and uncontrollable factors. PH was divided into five groups according to its pathogenesis and clinical manifestations. Although the treatment and diagnosis of PH has made great progress in the past ten years. However, the diagnosis and prognosis of the PAH had a great contrast, which was not conducive to the diagnosis and treatment of PH. If not treated properly, it will lead to right ventricular failure or even death. Therefore, it was necessary to explore the pathogenesis of PH. The problem we urgently need to solve was to find and develop drugs for the treatment of PH. We reviewed the PH articles in the past 10 years or so as well as systematically summarized the recent advance. We summarized the latest research on the key regulatory factors (pyroptosis, apoptosis, necroptosis, ferroptosis, and endoplasmic reticulum stress) involved in PH. To provide theoretical basis and basis for finding new therapeutic targets and research directions of PH.
Bioinspired crowding directs supramolecular polymerisation
Authors: Bäumer Nils , Castellanos Eduardo , Soberats Bartolome , Fernández Gustavo
Published: February 2023

Crowding effects are crucial to maintaining functionality in biological systems, but little is known about their role in analogous artificial counterparts. Within the growing field of supramolecular polymer science, crowding effects have hitherto remained underappreciated. Herein, we show that crowding effects exhibit strong and distinct control over the kinetics, accessible pathways and final outcomes of supramolecular polymerisation processes. In the presence of a pre-formed supramolecular polymer as crowding agent, a model supramolecular polymer dramatically changes its self-assembly behaviour and undergoes a morphological transformation from bundled fibres into flower-like hierarchical assemblies, despite no co-assembly taking place. Notably, this new pathway can only be accessed in crowded environments and when the crowding agent exhibits a one-dimensional morphology. These results allow accessing diverse morphologies and properties in supramolecular polymers and pave the way towards a better understanding of high-precision self-assembly in nature.
Climate-induced range shifts drive adaptive response via spatio-temporal sieving of alleles
Authors: Luqman Hirzi , Wegmann Daniel , Fior Simone , Widmer Alex
Published: February 2023

Quaternary climate fluctuations drove many species to shift their geographic ranges, in turn shaping their genetic structures. Recently, it has been argued that adaptation may have accompanied species range shifts via the “sieving” of genotypes during colonisation and establishment. However, this has not been directly demonstrated, and knowledge remains limited on how different evolutionary forces, which are typically investigated separately, interacted to jointly mediate species responses to past climatic change. Here, through whole-genome re-sequencing of over 1200 individuals of the carnation Dianthus sylvestris coupled with integrated population genomic and gene-environment models, we reconstruct the past neutral and adaptive landscape of this species as it was shaped by the Quaternary glacial cycles. We show that adaptive responses emerged concomitantly with the post-glacial range shifts and expansions of this species in the last 20 thousand years. This was due to the heterogenous sieving of adaptive alleles across space and time, as populations expanded out of restrictive glacial refugia into the broader and more heterogeneous range of habitats available in the present-day inter-glacial. Our findings reveal a tightly-linked interplay of migration and adaptation under past climate-induced range shifts, which we show is key to understanding the spatial patterns of adaptive variation we see in species today.
The crucial role of adhesion in the transmigration of active droplets through interstitial orifices
Authors: Tiribocchi A. , Durve M. , Lauricella M. , Montessori A. , Marenduzzo D. , Succi S.
Published: February 2023

Active fluid droplets are a class of soft materials exhibiting autonomous motion sustained by an energy supply. Such systems have been shown to capture motility regimes typical of biological cells and are ideal candidates as building-block for the fabrication of soft biomimetic materials of interest in pharmacology, tissue engineering and lab on chip devices. While their behavior is well established in unconstrained environments, much less is known about their dynamics under strong confinement. Here, we numerically study the physics of a droplet of active polar fluid migrating within a microchannel hosting a constriction with adhesive properties, and report evidence of a striking variety of dynamic regimes and morphological features, whose properties crucially depend upon droplet speed and elasticity, degree of confinement within the constriction and adhesiveness to the pore. Our results suggest that non-uniform adhesion forces are instrumental in enabling the crossing through narrow orifices, in contrast to larger gaps where a careful balance between speed and elasticity is sufficient to guarantee the transition. These observations may be useful for improving the design of artificial micro-swimmers, of interest in material science and pharmaceutics, and potentially for cell sorting in microfluidic devices.
Intra-pituitary follicle-stimulating hormone signaling regulates hepatic lipid metabolism in mice
Authors: Qiao Sen , Alasmi Samer , Wyatt Amanda , Wartenberg Philipp , Wang Hongmei , Candlish Michael , Das Debajyoti , Aoki Mari , Grünewald Ramona , Zhou Ziyue , Tian Qinghai , Yu Qiang , Götz Viktoria , Belkacemi Anouar , Raza Ahsan , Ectors Fabien , Kattler Kathrin , Gasparoni Gilles , Walter Jörn , Lipp Peter , Mollard Patrice , Bernard Daniel J. , Karatayli Ersin , Karatayli Senem Ceren , Lammert Frank , Boehm Ulrich
Published: February 2023

Inter-organ communication is a major hallmark of health and is often orchestrated by hormones released by the anterior pituitary gland. Pituitary gonadotropes secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH) to regulate gonadal function and control fertility. Whether FSH and LH also act on organs other than the gonads is debated. Here, we find that gonadotrope depletion in adult female mice triggers profound hypogonadism, obesity, glucose intolerance, fatty liver, and bone loss. The absence of sex steroids precipitates these phenotypes, with the notable exception of fatty liver, which results from ovary-independent actions of FSH. We uncover paracrine FSH action on pituitary corticotropes as a mechanism to restrain the production of corticosterone and prevent hepatic steatosis. Our data demonstrate that functional communication of two distinct hormone-secreting cell populations in the pituitary regulates hepatic lipid metabolism.
Cobalt(III)-catalyzed asymmetric ring-opening of 7-oxabenzonorbornadienes via indole C–H functionalization
Authors: Zheng Yang , Zhang Wen-Yun , Gu Qing , Zheng Chao , You Shu-Li
Published: February 2023

Asymmetric ring-opening of 7-oxabenzonorbornadienes is achieved via Co-catalyzed indole C–H functionalization. The utilization of chiral Co-catalyst consisting of a binaphthyl-derived trisubstituted cyclopentadienyl ligand resulted in high yields (up to 99%) and excellent enantioselectivity (>99% ee) for the target products with tolerance for diverse functional groups. Opposite diastereoselectivities are obtained with chiral Co-catalyst or Cp*CoI2CO. Combined experimental and computational studies suggest β-oxygen elimination being the selectivity-determining step of the reaction. Meanwhile, the reactions of 7-azabenzonorbornadiene could also be executed in a diastereodivergent manner.
Identification of SARS-CoV-2 Mpro inhibitors containing P1’ 4-fluorobenzothiazole moiety highly active against SARS-CoV-2
Authors: Higashi-Kuwata Nobuyo , Tsuji Kohei , Hayashi Hironori , Bulut Haydar , Kiso Maki , Imai Masaki , Ogata-Aoki Hiromi , Ishii Takahiro , Kobayakawa Takuya , Nakano Kenta , Takamune Nobutoki , Kishimoto Naoki , Hattori Shin-ichiro , Das Debananda , Uemura Yukari , Shimizu Yosuke , Aoki Manabu , Hasegawa Kazuya , Suzuki Satoshi , Nishiyama Akie , Saruwatari Junji , Shimizu Yukiko , Sukenaga Yoshikazu , Takamatsu Yuki , Tsuchiya Kiyoto , Maeda Kenji , Yoshimura Kazuhisa , Iida Shun , Ozono Seiya , Suzuki Tadaki , Okamura Tadashi , Misumi Shogo , Kawaoka Yoshihiro , Tamamura Hirokazu , Mitsuya Hiroaki
Published: February 2023

Abstract

COVID-19 caused by SARS-CoV-2 has continually been serious threat to public health worldwide. While a few anti-SARS-CoV-2 therapeutics are currently available, their antiviral potency is not sufficient. Here, we identify two orally available 4-fluoro-benzothiazole-containing small molecules, TKB245 and TKB248, which specifically inhibit the enzymatic activity of main protease (Mpro) of SARS-CoV-2 and significantly more potently block the infectivity and replication of various SARS-CoV-2 strains than nirmatrelvir, molnupiravir, and ensitrelvir in cell-based assays employing various target cells. Both compounds also block the replication of Delta and Omicron variants in human-ACE2-knocked-in mice. Native mass spectrometric analysis reveals that both compounds bind to dimer Mpro, apparently promoting Mpro dimerization. X-ray crystallographic analysis shows that both compounds bind to Mpro’s active-site cavity, forming a covalent bond with the catalytic amino acid Cys-145 with the 4-fluorine of the benzothiazole moiety pointed to solvent. The data suggest that TKB245 and TKB248 might serve as potential therapeutics for COVID-19 and shed light upon further optimization to develop more potent and safer anti-SARS-CoV-2 therapeutics.
A robust approach for MicroED sample preparation of lipidic cubic phase embedded membrane protein crystals
Authors: Martynowycz Michael W. , Shiriaeva Anna , Clabbers Max T. B. , Nicolas William J. , Weaver Sara J. , Hattne Johan , Gonen Tamir
Published: February 2023

Crystallizing G protein-coupled receptors (GPCRs) in lipidic cubic phase (LCP) often yields crystals suited for the cryogenic electron microscopy (cryoEM) method microcrystal electron diffraction (MicroED). However, sample preparation is challenging. Embedded crystals cannot be targeted topologically. Here, we use an integrated fluorescence light microscope (iFLM) inside of a focused ion beam and scanning electron microscope (FIB-SEM) to identify fluorescently labeled GPCR crystals. Crystals are targeted using the iFLM and LCP is milled using a plasma focused ion beam (pFIB). The optimal ion source for preparing biological lamellae is identified using standard crystals of proteinase K. Lamellae prepared using either argon or xenon produced the highest quality data and structures. MicroED data are collected from the milled lamellae and the structures are determined. This study outlines a robust approach to identify and mill membrane protein crystals for MicroED and demonstrates plasma ion-beam milling is a powerful tool for preparing biological lamellae.
BdLT-Seq as a barcode decay-based method to unravel lineage-linked transcriptome plasticity
Authors: Shlyakhtina Yelyzaveta , Bloechl Bianca , Portal Maximiliano M.
Published: February 2023

Cell plasticity is a core biological process underlying a myriad of molecular and cellular events taking place throughout organismal development and evolution. It has been postulated that cellular systems thrive to balance the organization of meta-stable states underlying this phenomenon, thereby maintaining a degree of populational homeostasis compatible with an ever-changing environment and, thus, life. Notably, albeit circumstantial evidence has been gathered in favour of the latter conceptual framework, a direct observation of meta-state dynamics and the biological consequences of such a process in generating non-genetic clonal diversity and divergent phenotypic output remains largely unexplored. To fill this void, here we develop a lineage-tracing technology termed Barcode decay Lineage Tracing-Seq. BdLT-Seq is based on episome-encoded molecular identifiers that, supported by the dynamic decay of the tracing information upon cell division, ascribe directionality to a cell lineage tree whilst directly coupling non-genetic molecular features to phenotypes in comparable genomic landscapes. We show that cell transcriptome states are both inherited, and dynamically reshaped following constrained rules encoded within the cell lineage in basal growth conditions, upon oncogene activation and throughout the process of reversible resistance to therapeutic cues thus adjusting phenotypic output leading to intra-clonal non-genetic diversity.
Membrane phospholipids control gating of the mechanosensitive potassium leak channel TREK1
Authors: Schmidpeter Philipp A. M. , Petroff John T. , Khajoueinejad Leila , Wague Aboubacar , Frankfater Cheryl , Cheng Wayland W. L. , Nimigean Crina M. , Riegelhaupt Paul M.
Published: February 2023

Tandem pore domain (K2P) potassium channels modulate resting membrane potentials and shape cellular excitability. For the mechanosensitive subfamily of K2Ps, the composition of phospholipids within the bilayer strongly influences channel activity. To examine the molecular details of K2P lipid modulation, we solved cryo-EM structures of the TREK1 K2P channel bound to either the anionic lipid phosphatidic acid (PA) or the zwitterionic lipid phosphatidylethanolamine (PE). At the extracellular face of TREK1, a PA lipid inserts its hydrocarbon tail into a pocket behind the selectivity filter, causing a structural rearrangement that recapitulates mutations and pharmacology known to activate TREK1. At the cytoplasmic face, PA and PE lipids compete to modulate the conformation of the TREK1 TM4 gating helix. Our findings demonstrate two distinct pathways by which anionic lipids enhance TREK1 activity and provide a framework for a model that integrates lipid gating with the effects of other mechanosensitive K2P modulators.
Long non-coding RNA-derived peptides are immunogenic and drive a potent anti-tumour response
Authors: Barczak Wojciech , Carr Simon M. , Liu Geng , Munro Shonagh , Nicastri Annalisa , Lee Lian Ni , Hutchings Claire , Ternette Nicola , Klenerman Paul , Kanapin Alexander , Samsonova Anastasia , La Thangue Nicholas B.
Published: February 2023

Protein arginine methyltransferase (PRMT) 5 is over-expressed in a variety of cancers and the master transcription regulator E2F1 is an important methylation target. We have explored the role of PRMT5 and E2F1 in regulating the non-coding genome and report here a striking effect on long non-coding (lnc) RNA gene expression. Moreover, many MHC class I protein-associated peptides were derived from small open reading frames in the lncRNA genes. Pharmacological inhibition of PRMT5 or adjusting E2F1 levels qualitatively altered the repertoire of lncRNA-derived peptide antigens displayed by tumour cells. When presented to the immune system as either ex vivo-loaded dendritic cells or expressed from a viral vector, lncRNA-derived peptides drove a potent antigen-specific CD8 T lymphocyte response, which translated into a significant delay in tumour growth. Thus, lncRNA genes encode immunogenic peptides that can be deployed as a cancer vaccine.
Softness of hydrated salt crystals under deliquescence
Authors: Wijnhorst Rozeline , Demmenie Menno , Jambon-Puillet Etienne , Ariese Freek , Bonn Daniel , Shahidzadeh Noushine
Published: February 2023

Deliquescence is a first-order phase transition, happening when a salt absorbs water vapor. This has a major impact on the stability of crystalline powders that are important for example in pharmacology, food science and for our environment and climate. Here we show that during deliquescence, the abundant salt sodium sulfate decahydrate, mirabilite (Na2SO4·10H2O), behaves differently than anhydrous salts. Using various microscopy techniques combined with Raman spectroscopy, we show that mirabilite crystals not only lose their facets but also become soft and deformable. As a result, microcrystals of mirabilite simultaneously behave crystalline-like in the core bulk and liquid-like at the surface. Defects at the surface can heal at a speed much faster than the deliquescence rate by the mechanism of visco-capillary flow over the surface. While magnesium sulfate hexahydrate (MgSO4⋅6H2O) behaves similarly during deliquescence, a soft and deformable state is completely absent for the anhydrous salts sodium chloride (NaCl) and sodium sulfate thenardite (Na2SO4). The results highlight the effect of crystalline water, and its mobility in the crystalline structure on the observed softness during deliquescence. Controlled hydrated salts have potential applications such as thermal energy storage, where the key parameter is relative humidity rather than temperature.
Anion-enrichment interface enables high-voltage anode-free lithium metal batteries
Authors: Mao Minglei , Ji Xiao , Wang Qiyu , Lin Zejing , Li Meiying , Liu Tao , Wang Chengliang , Hu Yong-Sheng , Li Hong , Huang Xuejie , Chen Liquan , Suo Liumin
Published: February 2023

Aggressive chemistry involving Li metal anode (LMA) and high-voltage LiNi0.8Mn0.1Co0.1O2 (NCM811) cathode is deemed as a pragmatic approach to pursue the desperate 400 Wh kg−1. Yet, their implementation is plagued by low Coulombic efficiency and inferior cycling stability. Herein, we propose an optimally fluorinated linear carboxylic ester (ethyl 3,3,3-trifluoropropanoate, FEP) paired with weakly solvating fluoroethylene carbonate and dissociated lithium salts (LiBF4 and LiDFOB) to prepare a weakly solvating and dissociated electrolyte. An anion-enrichment interface prompts more anions’ decomposition in the inner Helmholtz plane and higher reduction potential of anions. Consequently, the anion-derived interface chemistry contributes to the compact and columnar-structure Li deposits with a high CE of 98.7% and stable cycling of 4.6 V NCM811 and LiCoO2 cathode. Accordingly, industrial anode-free pouch cells under harsh testing conditions deliver a high energy of 442.5 Wh kg−1 with 80% capacity retention after 100 cycles.