bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction Models for Individual-Level Healthcare Costs Associated with Cardiovascular Events in the UK
Authors: Zhou Junwen , Wu Runguo , Williams Claire , Emberson Jonathan , Reith Christina , Keech Anthony , Robson John , Wilkinson Kenneth , Armitage Jane , Gray Alastair , Simes John , Baigent Colin , Mihaylova Borislava
Published: February 2023

Objectives

The aim of this study was to develop prediction models for the individual-level impacts of cardiovascular events on UK healthcare costs.

Methods

In the UK Biobank, people 40–70 years old, recruited in 2006–2010, were followed in linked primary (N = 192,983 individuals) and hospital care (N = 501,807 individuals) datasets. Regression models of annual primary and annual hospital care costs (2020 UK£) associated with individual characteristics and experiences of myocardial infarction (MI), stroke, coronary revascularization, incident diabetes mellitus and cancer, and vascular and nonvascular death are reported.

Results

For both people without and with previous cardiovascular disease (CVD), primary care costs were modelled using one-part generalised linear models (GLMs) with identity link and Poisson distribution, and hospital costs with two-part models (part 1: logistic regression models the probability of incurring costs; part 2: GLM with identity link and Poisson distribution models the costs conditional on incurring any). In people without previous CVD, mean annual primary and hospital care costs were £360 and £514, respectively. The excess primary care costs were £190 and £360 following MI and stroke, respectively, whereas excess hospital costs decreased from £4340 and £5590, respectively, in the year of these events, to £190 and £410 two years later. People with previous CVD had more than twice higher annual costs, and incurred higher excess costs for cardiovascular events. Other characteristics associated with higher costs included older age, female sex, south Asian ethnicity, higher socioeconomic deprivation, smoking, lower level of physical activities, unhealthy body mass index, and comorbidities.

Conclusions

These individual-level healthcare cost prediction models could inform assessments of the value of health technologies and policies to reduce cardiovascular and other disease risks and healthcare costs. An accompanying Excel calculator is available to facilitate the use of the models.
Urinary nephrin—a potential marker of early glomerular injury: a systematic review and meta-analysis
Authors: Mesfine Belete Biadgo , Vojisavljevic Danica , Kapoor Ranjna , Watson David , Kandasamy Yogavijayan , Rudd Donna
Published: February 2023

Background

Both early recognition of glomerular injury and diagnosis of renal injury remain important problems in clinical settings, and current diagnostic biomarkers have limitations. The aim of this review was to determine the diagnostic accuracy of urinary nephrin for detecting early glomerular injury.

Methods

A search was conducted through electronic databases for all relevant studies published until January 31, 2022. The methodological quality was evaluated using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Pooled sensitivity, specificity, and other estimates of diagnostic accuracy were determined using a random effect model. The Summary Receiver Operating Characteristics (SROC) was used to pool the data and to estimate the area under the curve (AUC).

Results

The meta-analysis included 15 studies involving 1587 participants. Overall, the pooled sensitivity of urinary nephrin for detecting glomerular injury was 0.86 (95% CI 0.83–0.89) and specificity was 0.73 (95% CI 0.70–0.76). The AUC-SROC to summarise the diagnostic accuracy was 0.90. As a predictor of preeclampsia, urinary nephrin showed a sensitivity of 0.78 (95% CI 0.71–0.84) and specificity of 0.79 (95% CI 0.75–0.82), and as a predictor of nephropathy the sensitivity was 0.90 (95% CI 0.87–0.93), and specificity was 0.62 (95% CI 0.56–0.67). A subgroup analysis using ELISA as a method of diagnosis showed a sensitivity of 0.89 (95% CI 0.86–0.92), and a specificity of 0.72 (95% CI 0.69–0.75).

Conclusion

Urinary nephrin may be a promising marker for the detection of early glomerular injury. ELISA assays appear to provide reasonable sensitivity and specificity. Once translated into clinical practice, urinary nephrin could provide an important addition to a panel of novel markers to help in the detection of acute and chronic renal injury.

Graphical abstract
Effect of chemical corrosion on propagation of complex fracture networks under different hydraulic pressures in enhanced geothermal systems
Authors: Liu Lanfu , Li Zhicong , Wu Jiangyu , Yu Liyuan , Li Shuchen , Liu Richeng
Published: February 2023

Chemical corrosion and hydraulic fracturing are important ways to improve the permeability of the enhanced geothermal systems. In this work, we developed a discrete element code for simulating the hydraulic fracturing of three different fracture network models after chemical corrosion. Mechanisms of the crack extension and coalescence in the field-scale models with fracture network were systematically revealed, in which the effects of corrosion time, inclination of the fracture (γ), pH value and hydraulic pressure were considered. The results show that the simulated cracking behaviors of granites agree well with those obtained through Brazilian tests and triaxial compression tests, verifying the validity of the developed discrete element code. During hydraulic fracturing, the impact of γ on the fracture network connectivity increases with the increment of hydraulic pressure (Pin). With the increase in hydraulic pressure, crack propagation accelerates whereas the connectivity of fracture network models decreases. The reasons are that the excessive hydraulic pressure causes the crack to spread in an unfavorable direction and increases the effect of γ on the connectivity of models of fracture networks. As the pH value increases from 2 to 12, the crack growth rate first decreases and subsequently raises. The numbers of cracks per time step of sparse mixed fracture networks with artificial fractures (SM), dense mixed fracture networks with artificial fractures (DM) and dense mixed fracture networks without artificial fractures (NDM) are in the ranges of 0.06601–0.1259, 0.05176–0.2072 and 0.1727–0.6846, respectively. The connectivity of SM is better than that of NDM under the same hydraulic fracturing conditions, indicating that artificial fractures can greatly improve the fracture network connectivity and the utilization efficiency of EGS.
Design and guidance of a multi-active debris removal mission
Authors: Wijayatunga Minduli C. , Armellin Roberto , Holt Harry , Pirovano Laura , Lidtke Aleksander A.
Published: February 2023

Space debris have become exceedingly dangerous over the years as the number of objects in orbit continues to increase. Active debris removal (ADR) missions have gained significant interest as effective means of mitigating the risk of collision between objects in space. This study focuses on developing a multi-ADR mission that utilizes controlled reentry and deorbiting. The mission comprises two spacecraft: a Servicer that brings debris to a low altitude and a Shepherd that rendezvous with the debris to later perform a controlled reentry. A preliminary mission design tool (PMDT) was developed to obtain time and fuel optimal trajectories for the proposed mission while considering the effect of J2, drag, eclipses, and duty cycle. The PMDT can perform such trajectory optimizations for multi-debris missions with computational time under a minute. Three guidance schemes are also studied, taking the PMDT solution as a reference to validate the design methodology and provide guidance solutions to this complex mission profile.
Natural Frequency Perturbations Using a Scalar Expression with Reference Plots to Predict Associated Errors
Authors: Kaminski Allison , McDaniel J. Gregory
Published: February 2023

Purpose

Eigenvalues are the natural frequencies of system squared. When designing a system it is important to know the natural frequencies, because if the system is forced near one of these natural frequencies the magnitude of vibration becomes very large. The eigenvalues are typically determined by solving an eigenvalue problem, which is an iterative produce that is expensive for larger systems. If multiple perturbations to the system are made or tested re-solving an eigenvalue problem every time becomes prohibitive. Perturbation methods exist to predict perturbed eigenvalues more quickly. However, these methods typically require matrix–vector products and do not quantify what is considered a small enough perturbation to use these methods.

Methods

This paper looks to address these issues using a scalar perturbed eigenvalue expression that avoids calculating matrix–vector products for every perturbation and developing reference plots that can be used to predict the associated error. The reference plots may be used to predict errors in the approximated natural frequencies from nominal modal parameters. The scalar perturbed eigenvalue expression and reference plots for errors were tested using numerical examples.

Results

In every case tested the plots were able to accurately predict the expected errors, to be within a predicted range.

Conclusion

The proposed method allows one to use the developed scalar expression to predict perturbed eigenvalues, and the developed reference plots may be used to predict the errors associated with using the proposed expression.
Evolution of δ phase precipitates in Inconel 625 superalloy additively manufactured by laser powder bed fusion and its modeling with fuzzy logic
Authors: Staroń Sylwia , Macioł Piotr , Dubiel Beata , Gola Kewin , Falkus Jan
Published: February 2023

Experimental and modeling studies of the evolution of plate-like δ phase precipitates in Inconel 625 superalloy additively manufactured by the laser powder bed fusion process are performed. The maximum Feret diameter and the number of particles per unit area are used as parameters describing the size and distribution of the δ phase precipitates. On the basis of microstructural analysis and quantitative image analysis, the effect of time and temperature on the development of δ phase precipitates is determined. The distinct differences in the intensity of precipitation, growth, and coarsening of the δ phase precipitates during annealing at temperatures of 700 and 800 °C up to 2000 h are shown. The experimental results are compared with computational data obtained by thermodynamic modeling. Using the experimentally determined parameters of the δ phase precipitates in different variants of annealing, a fuzzy logic-based phase distribution model is designed. Since the quantity of available data was too small to train a model with the machine learning approach, expert knowledge is used to design the rules, while numerical data are used for its validation. Designed rules, as well as reasoning methodology are described. The proposed model is validated by comparing it with the experimental results. It can be used to predict the size and number density of the δ phase precipitates in the additively manufactured Inconel 625, subjected to long-term annealing at temperatures of 700–800 °C. Due to limited experimental data, the quality of assurance is not perfect, but warrants preliminary research.

Graphical abstract
Output-based adaptive distributed observer for general linear leader systems over periodic switching digraphs
Authors: He Changran , Huang Jie
Published: February 2023

In this paper, we present a sufficient condition for the exponential stability of a class of linear switched systems. As an application of this stability result, we establish an output-based adaptive distributed observer for a general linear leader system over a periodic jointly connected switching communication network, which extends the applicability of the output-based adaptive distributed observer from a marginally stable linear leader system to any linear leader system and from an undirected switching graph to a directed switching graph. This output-based adaptive distributed observer will be applied to solve the leader-following consensus problem for multiple double-integrator systems.
The Maximal Product in Cubic Fuzzy Graph Structures with an Application
Authors: Rao Yongsheng , Akhoundi Maryam , Talebi Ali Asghar , Sadati Seyed Hossein
Published: February 2023

The cubic fuzzy graph structure, as a combination of cubic fuzzy graphs and fuzzy graph structures, shows better capabilities in solving complex problems, especially in cases where there are multiple relationships. The quality and method of determining the degree of vertices in this type of fuzzy graphs simultaneously supports fuzzy membership and interval-valued fuzzy membership, in addition to the multiplicity of relations, motivated us to conduct a study on the maximal product of cubic fuzzy graph structures. In this research, upon introducing the cubic fuzzy graph structure, some properties of the maximal product and its characteristics have been investigated. By introducing the degree and the total degree of a vertex in the product of at most two cubic fuzzy graph structures, its calculation methods are categorized based on different conditions among the membership functions of vertices and edges. The results show that all features of two cubic fuzzy graph structures do not appear in their maximal product and vice versa. Finally, an application of cubic fuzzy graph structure in project management is presented.
Study of the Variables of Local Healthcare Personnel Linked to Becoming a Formal Public CPR Instructor in Baoan, Shenzhen, China
Authors: Lin Jinle , wang Conghua , Luo Yi , Zhang Wenwu , Dou Qingli , Wei Jian , Fu Xuan , Tao Wuyuan
Published: February 2023

Background

Public Cardiopulmonary resuscitation (CPR) education is important to increase the survival rate of out-of-hospital cardiac arrest (OHCA). In this study, we survey local healthcare personnel in China who met the requirements of becoming public CPR instructors to assess their level of knowledge and attitudes toward teaching CPR.

Materials and Methods

To find qualified public CPR instructors among the local healthcare personnel, we ran three training sessions between March 2018 and December 2018. We held three courses on selecting public CPR instructors from the local healthcare personnel (n = 496). We also surveyed candidates for public CPR instructors before making our final choice. The selected instructors were retrained for a single day in December 2021. The necessary information was exchanged with the members of the passing group, and the maintained valuables were investigated.

Results

Public CPR instructors certified 428 cases (86.49%) after the final exam. The results showed that the emergency group had a higher success rate than the non-emergency group (control group) (175, 90.7% vs. 253, 83.8%; P = 0.042). Here, we conducted a binary logistic regression analysis to determine the relationship between 15 survey variables and the passing rate. The variables, such as financial incentives, prior automatic external defibrillator (AED) training, and younger age were independently affected by being public CPR instructors. Despite this, 246 instructors (57.9%) still attended the retraining courses in 2021, with significantly more instructors in the emergency group than those in the non-emergency group (111, 64.5% vs. 135, 53.4%; P = 0.022). Furthermore, the instructors who were not incentivized financially were less likely to switch between the emergency and non-emergency groups (96, 79.33% vs. 116, 86.56%; P = 0.990).

Conclusion

The Chinese emergency team can serve as a model for the local healthcare personnel by training and leading a group of volunteer CPR instructors. Our research has practical implications for China's national CPR education policy by informing the scheduling of regional public CPR education programs.
Pragmatics in Translation
Authors: Dayter Daria , Locher Miriam A. , Messerli Thomas C.
Published: February 2023

This Element addresses translation issues within an interpersonal pragmatics frame. The aims of this Element are twofold: first, we survey the current state of the field of pragmatics in translation; second, we present the current and methodologically innovative avenues of research in the field. We focus on three pragmatics issues – relational work, participation structure, and mediality – that we foreground as promising loci of research on translational data. By reviewing the trajectory of pragmatics research on translation/interpreting over time, and then outlining our understanding of the Pragmatics in Translation as a field, we arrive at a set of potential research questions which represent desiderata for future research. These questions identify the paths that can be productively explored through synergies of the linguistic pragmatics framework and translation data. In two case study chapters, we offer two example studies addressing some of the questions we identified as suggestions for future research. This title is also available as Open Access on Cambridge Core.
The Spaces of Bookselling
Authors: Highland Kristen Doyle
Published: February 2023

The spaces of bookselling have as many stories to tell as do the books for sale. More than static backgrounds for bookselling, these dynamic spaces both shape individual and collective behaviors and perceptions and are shaped by the values and practices of booksellers and book buyers. This Element focuses primarily on bookselling in the United States from the 19th through the 21st centuries and examines three key bookselling spaces-the store, the street, and the catalogue. Following an introduction, the second section considers how the material space of bookstores shapes social engagement in and cultural values associated with the bookstore. The third section turns to itinerant and sidewalk booksellers and the ways in which they use the physical, social, and legal space of the street to craft geographies of belonging. And the final section pages through bookseller catalogues, examining them as a significant genre that works to spatialize the bookstore.
Gabriel García Márquez and the Cinema
Authors: Rocco Alessandro
Published: February 2023

Rocco focuses on Gabriel García Márquez's relations with the world of cinema and gives us the first detailed study of the author's wide-ranging filmography.
How to Deal With the Risk of Evacuation of Psychiatric Hospital in Nuclear Disaster: A Case Study
Authors: Hori Arinobu , Sawano Toyoaki , Nonaka Saori , Tsubokura Masaharu
Published: February 2023

Objective:

People with psychiatric disorders are one of the most vulnerable populations in disasters, and the 2011 Great East Japan Earthquake reported higher post-evacuation mortality rates among psychiatric inpatients. A psychiatric hospital evacuated after the nuclear accident was surveyed to gain valuable insights for future disaster preparedness.

Methods:

The authors interviewed two Odaka Akasaka Hospital (a private psychiatric hospital) staff responsible for evacuation due to the nuclear accident.

Results:

At the time of the earthquake, 104 patients had been admitted to the hospital. They were instructed to evacuate on the grounds that they existed within a 20 km radius of Fukushima Daiichi Nuclear Power Station. Although the evacuation process was extraordinarily demanding, the staff acted professionally, and no patient experienced a significant deterioration in health during the evacuation.

Conclusion:

It was reasonable to follow the evacuation order because of the difficulty of obtaining accurate information about radiation exposure and staff availability in high-risk situations. The staff’s knowledgeable and attentive care of the patients was one of the factors that enabled them to successfully carry out this severe evacuation. However, this may be related to the high mortality rate after the evacuation of patients who were separated from such caregivers.
Is adolescent internet use a risk factor for the development of depression symptoms or vice-versa?
Authors: Fitzpatrick Caroline , Lemieux Annie , Smith Jonathan , West Greg L. , Bohbot Véronique , Asbridge Mark
Published: February 2023

Background

The extent to which digital media use by adolescents contributes to poor mental health, or vice-versa, remains unclear. The purpose of the present study is to clarify the strength and direction of associations between adolescent internet use and the development of depression symptoms using a longitudinal modeling approach. We also examine whether associations differ for boys and girls.

Methods

Data are drawn from (N = 1547) participants followed for the Quebec longitudinal Study of Child Development (QLSCD 1998–2020). Youth self-reported internet use in terms of the average hours of use per week at the ages of 13, 15, and 17. Youth also self-reported depression symptoms at the same ages.

Results

After testing sex-invariance, random intercepts cross-lagged panel models stratified by sex, revealed that internet use by girls was associated with significant within-person (time-varying) change in depression symptoms. Girl's internet use at age 13 was associated with increased depression symptoms at age 15 (ß = 0.12) and internet use at age 15 increased depression at age 17 (ß = 0.10). For boys, internet use was not associated with significant time varying change in depression symptoms.

Conclusions

The present findings support the hypothesis that internet use by adolescents can represent a significant risk factor for the development of depressive symptoms, particularly in girls.
Effectiveness of a cognitive–behavioral group therapy for complicated grief in relatives of patients with cancer: A randomized clinical trial
Authors: Lacasta María Antonia , Cruzado Juan Antonio
Published: February 2023

Introduction

Complicated grief can affect a large number of individuals who have lost a relative due to cancer.

Objectives

To assess the efficacy of a cognitive–behavioral grief therapy (CBGT) group for complicated grief (CG) in those who have lost a relative due to cancer in comparison with a psychoeducational and emotional expression intervention group (PSDEEI).

Methods

A randomized clinical trial was used, in which 249 relatives of deceased cancer patients with CG were randomly assigned to CBGT or PSDEEI. Complicated grief (Inventory of Complicated Grief [ICG]), depression (Beck Depression Inventory [BDI-II]), hopelessness (Beck Hopelessness Scale [BHS]), anxiety (Beck Anxiety Inventory [BAI]) symptoms, and general health (Goldberg’s General Health Questionnaire [GHQ28]) were assessed at pretreatment, posttreatment, and follow-up at 6 and 12 months.

Results

The CBGT group improved significantly (p < 0.001), with the scores in ICG, BDI-II, BAI, BHS, and GHQ28 (p < 0.001) being higher than those for the PSDEEI group in each of the assessed moments, with high effect sizes: ICG (η2 = 0.16), BDI (η2 = 0.10), BAI (η2 = 0.06), BHS (η2 = 0.21), and GHQ28 (η2 = 0.21). At the 12-month follow-up, the number of cases of CG decreased by 81.1% for the CBGT group vs. 31.7% in the PSDEEI group.

Significance of results

The CBGT treatment was effective for CG, depression, anxiety, and hopelessness symptoms and for mental health and was superior to the PSDEEI treatment.
Microstrip antennas on 3D-printed magneto-dielectric substrates: fabrication and efficiency study
Authors: Kakoyiannis Constantine , Sorocki Jakub , Piekarz Ilona , Geissler Matthias
Published: February 2023

Magneto-dielectric antennas (MDAs) provide small sizes, enhanced bandwidths, and frequency/polarization agility. We describe the fabrication and efficiency characterization at 0.4–0.8 GHz of five microstrip MDAs, whose gradually thicker substrates were 3D-printed using an off-the-shelf polylactic acid (PLA) filament doped with ferromagnetic particles. It was experimentally discovered that efficiency increases monotonically from 12% (−9.2 dB) to 37% (−4.3 dB) as substrate thickness goes from 1.6 to 4.3 mm; the rate is faster than expected for microstrip antennas. Numerical analysis indicated that the apparent magnetic loss tangent of the MD substrate experiences a threefold decrease as the 3D printer deposits more layers of iron-doped PLA. The MDAs exhibit radiation quality factors that are 3.7–7.2 times better than the dielectric counterparts. Moreover, a simple optimization of ground plane size could increase efficiency to 55% (−2.6 dB). The reduction in magnetic loss is attributed to a reduction in eddy current loss due to the separation of agglomerate iron particles. Therefore, despite the inherently lossy material used, the potential of 3D-printed MD substrates in providing acceptable antenna efficiencies is demonstrated together with unprecedented design freedom and fabrication flexibility.
The Agulhas Current Transports Signals of Local and Remote Indian Ocean Nitrogen Cycling
Authors: Marshall Tanya A. , Sigman Daniel M. , Beal Lisa M. , Foreman Alan , Martínez‐García Alfredo , Blain Stéphane , Campbell Ethan , Fripiat François , Granger Robyn , Harris Eesaa , Haug Gerald H. , Marconi Dario , Oleynik Sergey , Rafter Patrick A. , Roman Raymond , Sinyanya Kolisa , Smart Sandi M. , Fawcett Sarah E.
Published: February 2023

The greater Agulhas Current region is an important component of the climate system, yet its influence on carbon and nutrient cycling is poorly understood. Here, we use nitrate isotopes (δ15N, δ18O, Δ(15–18) = δ15N–δ18O) to trace regional water mass circulation and investigate nitrogen cycling in the Agulhas Current and adjacent recirculating waters. The deep and intermediate waters record processes occurring remotely, including partial nitrate assimilation in the Southern Ocean and denitrification in the Arabian Sea. In the thermocline and surface, tropically sourced waters are biogeochemically distinct from adjacent subtropically sourced waters, confirming inhibited lateral mixing across the current core. (Sub)tropical thermocline nitrate δ15N is lower (4.9–5.8‰) than the sub‐thermocline source, Subantarctic Mode Water (6.9‰); we attribute this difference to local N2 fixation. Using a one‐box model to simulate the newly fixed nitrate flux, we estimate a local N2 fixation rate of 7–25 Tg N.a−1, with the upper limit likely biased high. In the mixed layer, nitrate δ15N and δ18O rise in unison, indicating that phytoplankton nitrate assimilation dominates in surface waters, with nitrification restricted to deeper waters. Because nitrate assimilation and nitrification are vertically decoupled, the rate of nitrate assimilation plus N2 fixation can be used to approximate carbon export. Thermocline and mixed‐layer nitrate Δ(15–18) is low, due to both N2 fixation and coupled partial nitrate assimilation and nitrification. Similarly low‐Δ(15–18) nitrate in Agulhas rings indicates leakage of low‐δ15N nitrogen into the South Atlantic, which should be recorded in the organic matter sinking to the seafloor, providing a potential tracer of past Agulhas leakage.
Modeling Seasonal Effects of River Flow on Water Temperatures in an Agriculturally Dominated California River
Authors: Asarian J. Eli , Robinson Crystal , Genzoli Laurel
Published: February 2023

Low streamflows can increase vulnerability to warming, impacting coldwater fish. Water managers need tools to quantify these impacts and predict future water temperatures. Contrary to most statistical models' assumptions, many seasonally changing factors (e.g., water sources and solar radiation) cause relationships between flow and water temperature to vary throughout the year. Using 21 yr of air temperature and flow data, we modeled daily water temperatures in California's snowmelt‐driven Scott River where agricultural diversions consume most summer surface flows. We used generalized additive models to test time‐varying and nonlinear effects of flow on water temperatures. Models that represented seasonally varying flow effects with intermediate complexity outperformed simpler models assuming constant relationships between water temperature and flow. Cross‐validation error of the selected model was ≤1.2°C. Flow variation had stronger effects on water temperatures in April–July than in other months. We applied the model to predict effects of instream flow scenarios proposed by regulatory agencies. Relative to historic conditions, the higher instream flow scenario would reduce annual maximum temperature from 25.2° to 24.1°C, reduce annual exceedances of 22°C (a cumulative thermal stress metric) from 106 to 51 degree‐days, and delay onset of water temperatures >22°C during some drought years. Testing the same modeling approach at nine additional sites showed similar accuracy and flow effects. These methods can be applied to streams with long‐term flow and water temperature records to fill data gaps, identify periods of flow influence, and predict temperatures under flow management scenarios.
An agonistic anti-Tie2 antibody suppresses the normal-to-tumor vascular transition in the glioblastoma invasion zone
Authors: Lee Eunhyeong , Lee Eun-Ah , Kong Eunji , Chon Haemin , Llaiqui-Condori Melissa , Park Cheon Ho , Park Beom Yong , Kang Nu Ri , Yoo Jin-San , Lee Hyun-Soo , Kim Hyung-Seok , Park Sung-Hong , Choi Seung-Won , Vestweber Dietmar , Lee Jeong Ho , Kim Pilhan , Lee Weon Sup , Kim Injune
Published: February 2023

Tumor progression is intimately associated with the vasculature, as tumor proliferation induces angiogenesis and tumor cells metastasize to distant organs via blood vessels. However, whether tumor invasion is associated with blood vessels remains unknown. As glioblastoma (GBM) is featured by aggressive invasion and vascular abnormalities, we characterized the onset of vascular remodeling in the diffuse tumor infiltrating zone by establishing new spontaneous GBM models with robust invasion capacity. Normal brain vessels underwent a gradual transition to severely impaired tumor vessels at the GBM periphery over several days. Increasing vasodilation from the tumor periphery to the tumor core was also found in human GBM. The levels of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) showed a spatial correlation with the extent of vascular abnormalities spanning the tumor-invading zone. Blockade of VEGFR2 suppressed vascular remodeling at the tumor periphery, confirming the role of VEGF-VEGFR2 signaling in the invasion-associated vascular transition. As angiopoietin-2 (ANGPT2) was expressed in only a portion of the central tumor vessels, we developed a ligand-independent tunica interna endothelial cell kinase 2 (Tie2)-activating antibody that can result in Tie2 phosphorylation in vivo. This agonistic anti-Tie2 antibody effectively normalized the vasculature in both the tumor periphery and tumor center, similar to the effects of VEGFR2 blockade. Mechanistically, this antibody-based Tie2 activation induced VE-PTP-mediated VEGFR2 dephosphorylation in vivo. Thus, our study reveals that the normal-to-tumor vascular transition is spatiotemporally associated with GBM invasion and may be controlled by Tie2 activation via a novel mechanism of action.
TRAF3 activates STING-mediated suppression of EV-A71 and target of viral evasion
Authors: Zheng Wenwen , Zhou Zhenbang , Rui Yajuan , Ye Runxin , Xia Fengyan , Guo Fei , Liu Xiaoman , Su Jiaming , Lou Meng , Yu Xiao-Fang
Published: February 2023

Innate immunity represents one of the main host responses to viral infection.1–3 STING (Stimulator of interferon genes), a crucial immune adapter functioning in host cells, mediates cGAS (Cyclic GMP-AMP Synthase) sensing of exogenous and endogenous DNA fragments and generates innate immune responses.4 Whether STING activation was involved in infection and replication of enterovirus remains largely unknown. In the present study, we discovered that human enterovirus A71 (EV-A71) infection triggered STING activation in a cGAS dependent manner. EV-A71 infection caused mitochondrial damage and the discharge of mitochondrial DNA into the cytosol of infected cells. However, during EV-A71 infection, cGAS-STING activation was attenuated. EV-A71 proteins were screened and the viral protease 2Apro had the greatest capacity to inhibit cGAS-STING activation. We identified TRAF3 as an important factor during STING activation and as a target of 2Apro. Supplement of TRAF3 rescued cGAS-STING activation suppression by 2Apro. TRAF3 supported STING activation mediated TBK1 phosphorylation. Moreover, we found that 2Apro protease activity was essential for inhibiting STING activation. Furthermore, EV-D68 and CV-A16 infection also triggered STING activation. The viral protease 2Apro from EV-D68 and CV-A16 also had the ability to inhibit STING activation. As STING activation prior to EV-A71 infection generated cellular resistance to EV-A71 replication, blocking EV-A71-mediated STING suppression represents a new anti-viral target.
RETRACTED ARTICLE: Ibrutinib facilitates the sensitivity of colorectal cancer cells to ferroptosis through BTK/NRF2 pathway
Authors: Zhu Jin-Feng , Liu Yi , Li Wen-Ting , Li Ming-Hui , Zhen Chao-Hui , Sun Pei-Wei , Chen Ji-Xin , Wu Wen-Hao , Zeng Wei
Published: February 2023

Ibrutinib is a drug that inhibits the protein Burton’s tyrosine kinase and thereby the nuclear translocation of Nrf2, which played a key role in mediating the activation of antioxidants during stress conditions and ferroptosis resistance. This study aimed to identify the effect of Ibrutinib and ferroptosis inducer on colorectal cancer (CRC) treatment and its underlying mechanism. In our study, we found the upregulation of Nrf2 was correlated with CRC progression and antioxidant proteins. Ibrutinib sensitized CRC to ferroptosis inducers, suggested by further reduced CRC cell viability, proliferation and decreased antioxidant protein levels in CRC cells after combination treatment of Ibrutinib and RSL3 or Ibrutinib and Erastin both in vivo and in vitro. Knockout of Nrf2 diminished the regulatory effect of Ibrutinib on CRC sensitivity to ferroptosis inducers. Altogether, this study demonstrated that Ibrutinib increases the sensitivity of CRC cell to ferroptosis inducers by inhibiting Nrf2.
HOXC11 drives lung adenocarcinoma progression through transcriptional regulation of SPHK1
Authors: Peng Xin , Liu Xiaoli , Hu Wanshan , Zhou Yanling , Ouyang Lianlian , Peng Xintong , Long Yao , Sun Jingyue , Tao Tania , Chen Ling , Shi Ying , Tao Yongguang , Xiao Desheng , Liu Shuang
Published: February 2023

Lung adenocarcinoma (LUAD) is a fatal threat to human health, while the mechanism remains unclear, and the therapy brings limited therapeutic effects. Transcription factor Homeobox C11 (HOXC11) was previously proved to be related to hind limbs and metanephric development during the embryonic phase, and its role in tumors has been gradually recognized. Our study found that HOXC11 overexpressed in LUAD and was associated with worse overall survival. Moreover, its expression in lung cancer was regulated by IκB kinase α (IKKα), a pivotal kinase in NF-κB signaling, which was related to the ubiquitination of HOXC11. We further proved that HOXC11 could enhance the ability of proliferation, migration, invasion, colony formation, and the progression of the cell cycle in LUAD cells. Meanwhile, it also accelerated the formation of subcutaneous and lung metastases tumors. In contrast, loss of HOXC11 in LUAD cells significantly inhibited these malignant phenotypes. At the same time, HOXC11 regulated the expression of sphingosine kinase 1 (SPHK1) by directly binding to its promoter region. Therefore, we conclude that HOXC11 impacts the development of LUAD and facilitates lung cancer progression by promoting the expression of SPHK1.
A first-in-class POLRMT specific inhibitor IMT1 suppresses endometrial carcinoma cell growth
Authors: Li Shu-ping , Ou Li , Zhang Yan , Shen Fang-rong , Chen You-guo
Published: February 2023

Exploring novel molecularly-targeted therapies for endometrial carcinoma is important. The current study explored the potential anti-endometrial carcinoma activity by a first-in-class POLRMT (RNA polymerase mitochondrial) inhibitor IMT1. In patient-derived primary human endometrial carcinoma cells and established lines, treatment with IMT1 potently inhibited cell viability, proliferation, cell-cycle progression and motility, while inducing robust caspase-apoptosis activation. Treatment with the PLORMT inhibitor impaired mitochondrial functions, leading to mtDNA (mitochondrial DNA) transcription inhibition, mitochondrial membrane potential decline, reactive oxygen species formation, oxidative stress and ATP loss in the endometrial carcinoma cells. Similarly, POLRMT depletion, through shRNA-induced silencing or CRISPR/Cas9-caused knockout (KO), inhibited primary endometrial carcinoma cell proliferation and motility, and induced mitochondrial dysfunction and apoptosis. Importantly, IMT1 failed to induce further cytotoxicity in POLRMT-KO endometrial carcinoma cells. Contrarily, ectopic overexpression of POLRMT further augmented proliferation and motility of primary endometrial carcinoma cells. In vivo, oral administration of a single dose of IMT1 substantially inhibited endometrial carcinoma xenograft growth in the nude mice. mtDNA transcription inhibition, oxidative stress, ATP loss and apoptosis were detected in IMT1-treated endometrial carcinoma xenograft tissues. Together, targeting PLORMT by IMT1 inhibited endometrial carcinoma cell growth in vitro and in vivo.
Identification of matrix-remodeling associated 5 as a possible molecular oncotarget of pancreatic cancer
Authors: Peng Shi-qing , Zhu Xiao-ren , Zhao Ming-zhi , Zhang Yi-fan , Wang An-ran , Chen Min-bin , Ye Zhen-yu
Published: February 2023

Pancreatic cancer has an extremely poor prognosis. Here we examined expression, potential functions and underlying mechanisms of MXRA5 (matrix remodeling associated 5) in pancreatic cancer. Bioinformatics studies revealed that MXRA5 transcripts are significantly elevated in pancreatic cancer tissues, correlating with the poor overall survival, high T-stage, N1 and pathologic stage of the patients. MXRA5 mRNA and protein expression is significantly elevated in microarray pancreatic cancer tissues and different pancreatic cancer cells. In primary and immortalized (BxPC-3 and PANC-1 lines) pancreatic cancer cells, shRNA-induced MXRA5 silencing or CRISPR/Cas9-mediated MXRA5 knockout suppressed cell survival, proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while provoking cell apoptosis. Conversely, forced overexpression of MXRA5 further promoted pancreatic cancer cell progression and EMT. Bioinformatics studies and the protein chip analyses revealed that differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in MXRA5-overexpressed primary pancreatic cancer cells were enriched in the PI3K-Akt-mTOR cascade. Indeed, Akt-mTOR activation in primary human pancreatic cancer cells was inhibited by MXRA5 shRNA or knockout, but was augmented following MXRA5 overexpression. In vivo, the growth of MXRA5 KO PANC-1 xenografts was largely inhibited in nude mice. Moreover, intratumoral injection of adeno-associated virus-packed MXRA5 shRNA potently inhibited primary pancreatic cancer cell growth in nude mice. Akt-mTOR activation was also largely inhibited in the MXRA5-depleted pancreatic cancer xenografts. Contrarily MXRA5 overexpression promoted primary pancreatic cancer cell growth in nude mice. Together, overexpressed MXRA5 is important for pancreatic cancer cell growth possibly through promoting EMT and Akt-mTOR activation. MXRA5 could be a potential therapeutic oncotarget for pancreatic cancer.
Dark microbiome and extremely low organics in Atacama fossil delta unveil Mars life detection limits
Authors: Azua-Bustos Armando , Fairén Alberto G. , González-Silva Carlos , Prieto-Ballesteros Olga , Carrizo Daniel , Sánchez-García Laura , Parro Victor , Fernández-Martínez Miguel Ángel , Escudero Cristina , Muñoz-Iglesias Victoria , Fernández-Sampedro Maite , Molina Antonio , Villadangos Miriam García , Moreno-Paz Mercedes , Wierzchos Jacek , Ascaso Carmen , Fornaro Teresa , Brucato John Robert , Poggiali Giovanni , Manrique Jose Antonio , Veneranda Marco , López-Reyes Guillermo , Sanz-Arranz Aurelio , Rull Fernando , Ollila Ann M. , Wiens Roger C. , Reyes-Newell Adriana , Clegg Samuel M. , Millan Maëva , Johnson Sarah Stewart , McIntosh Ophélie , Szopa Cyril , Freissinet Caroline , Sekine Yasuhito , Fukushi Keisuke , Morida Koki , Inoue Kosuke , Sakuma Hiroshi , Rampe Elizabeth
Published: February 2023

Identifying unequivocal signs of life on Mars is one of the most important objectives for sending missions to the red planet. Here we report Red Stone, a 163-100 My alluvial fan–fan delta that formed under arid conditions in the Atacama Desert, rich in hematite and mudstones containing clays such as vermiculite and smectites, and therefore geologically analogous to Mars. We show that Red Stone samples display an important number of microorganisms with an unusual high rate of phylogenetic indeterminacy, what we refer to as “dark microbiome”, and a mix of biosignatures from extant and ancient microorganisms that can be barely detected with state-of-the-art laboratory equipment. Our analyses by testbed instruments that are on or will be sent to Mars unveil that although the mineralogy of Red Stone matches that detected by ground-based instruments on the red planet, similarly low levels of organics will be hard, if not impossible to detect in Martian rocks depending on the instrument and technique used. Our results stress the importance in returning samples to Earth for conclusively addressing whether life ever existed on Mars.
Social complexity, life-history and lineage influence the molecular basis of castes in vespid wasps
Authors: Wyatt Christopher Douglas Robert , Bentley Michael Andrew , Taylor Daisy , Favreau Emeline , Brock Ryan Edward , Taylor Benjamin Aaron , Bell Emily , Leadbeater Ellouise , Sumner Seirian
Published: February 2023

A key mechanistic hypothesis for the evolution of division of labour in social insects is that a shared set of genes co-opted from a common solitary ancestral ground plan (a genetic toolkit for sociality) regulates caste differentiation across levels of social complexity. Using brain transcriptome data from nine species of vespid wasps, we test for overlap in differentially expressed caste genes and use machine learning models to predict castes using different gene sets. We find evidence of a shared genetic toolkit across species representing different levels of social complexity. We also find evidence of additional fine-scale differences in predictive gene sets, functional enrichment and rates of gene evolution that are related to level of social complexity, lineage and of colony founding. These results suggest that the concept of a shared genetic toolkit for sociality may be too simplistic to fully describe the process of the major transition to sociality.
Variant Plateau’s law in atomically thin transition metal dichalcogenide dome networks
Authors: Liu Boqing , Yildirim Tanju , Lü Tieyu , Blundo Elena , Wang Li , Jiang Lixue , Zou Hongshuai , Zhang Lijun , Zhao Huijun , Yin Zongyou , Tian Fangbao , Polimeni Antonio , Lu Yuerui
Published: February 2023

Since its fundamental inception from soap bubbles, Plateau’s law has sparked extensive research in equilibrated states. However, most studies primarily relied on liquids, foams or cellular structures, whereas its applicability has yet to be explored in nano-scale solid films. Here, we observed a variant Plateau’s law in networks of atomically thin domes made of solid two-dimensional (2D) transition metal dichalcogenides (TMDs). Discrete layer-dependent van der Waals (vdWs) interaction energies were experimentally and theoretically obtained for domes protruding in different TMD layers. Significant surface tension differences from layer-dependent vdWs interaction energies manifest in a variant of this fundamental law. The equivalent surface tension ranges from 2.4 to 3.6 N/m, around two orders of magnitude greater than conventional liquid films, enabling domes to sustain high gas pressure and exist in a fundamentally variant nature for several years. Our findings pave the way towards exploring variant discretised states with applications in opto-electro-mechanical devices.
A bivalent remipede toxin promotes calcium release via ryanodine receptor activation
Authors: Maxwell Michael J. , Thekkedam Chris , Lamboley Cedric , Chin Yanni K.-Y. , Crawford Theo , Smith Jennifer J. , Liu Junyu , Jia Xinying , Vetter Irina , Laver Derek R. , Launikonis Bradley S. , Dulhunty Angela , Undheim Eivind A. B. , Mobli Mehdi
Published: February 2023

Multivalent ligands of ion channels have proven to be both very rare and highly valuable in yielding unique insights into channel structure and pharmacology. Here, we describe a bivalent peptide from the venom of Xibalbanus tulumensis, a troglobitic arthropod from the enigmatic class Remipedia, that causes persistent calcium release by activation of ion channels involved in muscle contraction. The high-resolution solution structure of φ-Xibalbin3-Xt3a reveals a tandem repeat arrangement of inhibitor-cysteine knot (ICK) domains previously only found in spider venoms. The individual repeats of Xt3a share sequence similarity with a family of scorpion toxins that target ryanodine receptors (RyR). Single-channel electrophysiology and quantification of released Ca2+ stores within skinned muscle fibers confirm Xt3a as a bivalent RyR modulator. Our results reveal convergent evolution of RyR targeting toxins in remipede and scorpion venoms, while the tandem-ICK repeat architecture is an evolutionary innovation that is convergent with toxins from spider venoms.
Abstract representations emerge naturally in neural networks trained to perform multiple tasks
Authors: Johnston W. Jeffrey , Fusi Stefano
Published: February 2023

Humans and other animals demonstrate a remarkable ability to generalize knowledge across distinct contexts and objects during natural behavior. We posit that this ability to generalize arises from a specific representational geometry, that we call abstract and that is referred to as disentangled in machine learning. These abstract representations have been observed in recent neurophysiological studies. However, it is unknown how they emerge. Here, using feedforward neural networks, we demonstrate that the learning of multiple tasks causes abstract representations to emerge, using both supervised and reinforcement learning. We show that these abstract representations enable few-sample learning and reliable generalization on novel tasks. We conclude that abstract representations of sensory and cognitive variables may emerge from the multiple behaviors that animals exhibit in the natural world, and, as a consequence, could be pervasive in high-level brain regions. We also make several specific predictions about which variables will be represented abstractly.
Attosecond-Angstrom free-electron-laser towards the cold beam limit
Authors: Habib A. F. , Manahan G. G. , Scherkl P. , Heinemann T. , Sutherland A. , Altuiri R. , Alotaibi B. M. , Litos M. , Cary J. , Raubenheimer T. , Hemsing E. , Hogan M. J. , Rosenzweig J. B. , Williams P. H. , McNeil B. W. J. , Hidding B.
Published: February 2023

Electron beam quality is paramount for X-ray pulse production in free-electron-lasers (FELs). State-of-the-art linear accelerators (linacs) can deliver multi-GeV electron beams with sufficient quality for hard X-ray-FELs, albeit requiring km-scale setups, whereas plasma-based accelerators can produce multi-GeV electron beams on metre-scale distances, and begin to reach beam qualities sufficient for EUV FELs. Here we show, that electron beams from plasma photocathodes many orders of magnitude brighter than state-of-the-art can be generated in plasma wakefield accelerators (PWFAs), and then extracted, captured, transported and injected into undulators without significant quality loss. These ultrabright, sub-femtosecond electron beams can drive hard X-FELs near the cold beam limit to generate coherent X-ray pulses of attosecond-Angstrom class, reaching saturation after only 10 metres of undulator. This plasma-X-FEL opens pathways for advanced photon science capabilities, such as unperturbed observation of electronic motion inside atoms at their natural time and length scale, and towards higher photon energies.