bluuebunny/crossref_metadata_2025 huggingface dataset:
Revisiting prognostic factors in glioma with leptomeningeal metastases: a comprehensive analysis of clinical and molecular factors and treatment modalities
Authors: Park Yae Won , Han Kyunghwa , Kim Sooyon , Kwon Hyuk , Ahn Sung Soo , Moon Ju Hyung , Kim Eui Hyun , Kim Jinna , Kang Seok-Gu , Chang Jong Hee , Kim Se Hoon , Lee Seung-Koo
Published: February 2023

Purpose

To comprehensively investigate prognostic factors, including clinical and molecular factors and treatment modalities, in adult glioma patients with leptomeningeal metastases (LM).

Methods

Total 226 patients with LM (from 2001 to 2021 among 1495 grade 2 to 4 glioma patients, 88.5% of LM patients being IDH-wildtype) with complete information on IDH mutation, 1p/19q codeletion, and MGMT promoter methylation status were enrolled. Predictors of overall survival (OS) of entire patients were determined by time-dependent Cox analysis, including clinical, molecular, and treatment data. Subgroup analyses were performed for patients with LM at initial diagnosis and LM diagnosed at recurrence (herein, initial and recurrent LM). Identical analyses were performed in IDH-wildtype glioblastoma patients.

Results

Median OS was 17.0 (IQR 9.7–67.1) months, with shorter median OS in initial LM than recurrent LM patients (12.2 vs 20.6 months, P < 0.001). In entire patients, chemotherapy and antiangiogenic therapy were predictors of longer OS, while male sex and initial LM were predictors of shorter OS. In initial LM, higher KPS, chemotherapy, and antiangiogenic therapy were predictors of longer OS, while male sex was a predictor of shorter OS. In recurrent LM, chemotherapy and longer interval between initial glioma and LM diagnoses were predictors of longer OS, while male sex was a predictor of shorter OS. A similar trend was observed in IDH-wildtype glioblastoma.

Conclusion

Active chemotherapy and antiangiogenic therapy demonstrated survival benefit in glioma patients with LM. There is consistent female survival advantage, whereas longer interval between initial glioma diagnosis and LM development suggests longer OS in recurrent LM.
Does temporary employment increase length of commuting? Longitudinal evidence from Australia and Germany
Authors: Laß Inga , Skora Thomas , Rüger Heiko , Wooden Mark , Bujard Martin
Published: February 2023

On average, temporary jobs are far less stable than permanent jobs. This higher instability could potentially lower workers’ incentives to relocate towards the workplace, thereby resulting in longer commutes. However, surprisingly few studies have investigated the link between temporary employment and commuting length. Building on the notion that individuals strive to optimize their utility when deciding where to work and live, we develop and test a theoretical framework that predicts commuting outcomes for different types of temporary workers – fixed-term, casual and temporary agency workers – and in different institutional contexts. We estimate fixed-effects regression models using 17 waves of data from the Household, Income and Labour Dynamics in Australia (HILDA) Survey and the German Socio-Economic Panel (SOEP). As expected, the results show that the link between temporary employment and commuting length varies by employment type and institutional context. Agency work is associated with longer commutes than permanent work in both countries, whereas this applies to fixed-term contracts for Germany only. For casual work, the findings suggest no commuting length differential to permanent employment. In terms of policy, our findings suggest lengthy commuting can be a side effect of flexible labour markets, with potentially negative implications for worker well-being, transportation management and the environment.
Impact of the Amount of the Gold Layer on the Tribological Performance of the Ceramic Conversion Treated CP-Titanium
Authors: Zhang Zhenxue , Yu Hao , Li Xiaoying , Dong Hanshan
Published: February 2023

Titanium alloys are characterised by poor tribological properties, and a ceramic TiO2 layer formed on the surface can greatly improve its performance. By pre-depositing a gold layer on the titanium surface, the gold particles promoted the outward diffusion of titanium in the ceramic conversion treatment to react with the inward-coming oxygen to form a compact titanium dioxide layer. The surface morphology, microstructure, and phase constituents were characterised by SEM/EDX and XRD. The adhesion of the oxide layers was assessed by a scratch test. The distribution of gold particles in the oxide layer enhanced the surface hardness and reduced the friction and wear against a WC (tungsten carbide) ball in the reciprocal tribological test. The ceramic conversion process was accelerated efficiently at 620–660 °C, and the more gold pre-deposited, the thicker the oxide layer.

Graphical Abstract
Increased Amount of Polyunsaturated Fatty Acids in the Intestinal Contents of Patients with Morbid Obesity
Authors: Janczy Agata , Szymanski Michal , Stankiewicz Marta , Kaska Lukasz , Waleron Krzysztof , Stelmanska Ewa , Sledzinski Tomasz , Mika Adriana
Published: February 2023

Introduction

Obesity is associated with disturbed gut microbiota homeostasis that translates into altered intestinal and blood metabolite profiles. The long-chain fatty acid (LCFA) may be absorbed in the intestine, but until now, their composition in intestinal contents of patients with obesity has not been studied. The aim of the present study was to verify whether obesity is related to any changes in fecal LCFA content and whether intestinal LCFA content may be associated with the health status of patients with obesity.

Methods

The fatty acid composition has been studied in stool samples obtained from 26 patients with morbid obesity and 25 lean subjects by gas chromatography–mass spectrometry. The dietary habits were assessed using the Food Frequency Questionnaire (FFQ-6).

Results

Our results show for the first time that lean subjects and patients with obesity differ in their stool LCFA profiles. The levels of most n-3 polyunsaturated fatty acids (PUFAs) and n-6 PUFAs were significantly higher in fecal samples from people with obesity than in those from lean controls.

Conclusions

Based on the current knowledge, we have defined three hypotheses that may explain proving the cause-and-effect relationships observed differences in fecal LCFA profiles between patients with obesity and lean subjects. They may be related to alterations in fat digestion and/or LCFA absorption and diet. However, proving the cause-and-effect relationships requires further research.

Graphical Abstract
Non-linear INAR(1) processes under an alternative geometric thinning operator
Authors: Barreto-Souza Wagner , Ndreca Sokol , Silva Rodrigo B. , Silva Roger W. C.
Published: February 2023

We propose a novel class of first-order integer-valued AutoRegressive (INAR(1)) models based on a new operator, the so-called geometric thinning operator, which induces a certain non-linearity to the models. We show that this non-linearity can produce better results in terms of prediction when compared to the linear case commonly considered in the literature. The new models are named non-linear INAR(1) (in short NonLINAR(1)) processes. We explore both stationary and non-stationary versions of the NonLINAR processes. Inference on the model parameters is addressed and the finite-sample behavior of the estimators investigated through Monte Carlo simulations. Two real data sets are analyzed to illustrate the stationary and non-stationary cases and the gain of the non-linearity induced for our method over the existing linear methods. A generalization of the geometric thinning operator and an associated NonLINAR process are also proposed and motivated for dealing with zero-inflated or zero-deflated count time series data.
Toward an understanding of occupational burnout among employees with autism – the Job Demands-Resources theory perspective
Authors: Tomczak Michał T. , Kulikowski Konrad
Published: February 2023

This article aims to gain insight into the phenomenon of occupational burnout among employees with autism based on the theoretical framework of the Job Demands-Resources theory and the literature on employees with autism in the workplace. Firstly, we argue that although the resources and demands of the neurotypical and neurodivergent employees might be different, the theoretical mechanism of occupational burnout formation remains similar among the neurotypical and neurodivergent employees, leading to the similar burnout experience. Next, we distinguish key demands that might drain neurodiverse employees’ energy, and spark burnout, and propose a set of resources that might foster their achievement of work goals and mitigate demanding working conditions. We emphasise that the nature of job demands/resources that may cause burnout is not universal but might depend on how employees evaluate them, thus neurotypical and neurodiverse workers who evaluate the same work characteristics differently might complement each other, increasing organisational diversity without losing productivity. Our conceptual elaboration contributes to the theory and practice of healthier workplaces by providing tools and inspiration to managers, policymakers, and all stakeholders interested in creating a diverse and productive workplace. Moreover, our work might spark a much needed debate on occupational burnout among employees with autism and encourage conducting further empirical studies.
Cell Death Markers in Children with Immune Thrombocytopenic Purpura: A Preliminary Study
Authors: Yahia Sohier , Eldars Waleed , Eldegla Heba , Mansour Ahmed K. , Guaida Mouna , Abdelkader Mohamed S. A. , Wahba Yahya
Published: February 2023

Immune thrombocytopenic purpura (ITP) is an autoimmune disease with possible dysregulation of the apoptotic pathways. We aimed to evaluate the possible role of some apoptotic markers (caspase 3, caspase 8 and BCL2) in the pathogenesis and course of ITP. We investigated some apoptotic markers (caspase 3, caspase 8 and BCL2) using the flow cytometry in 60 children with newly diagnosed ITP, 20 children with chemotherapy-related thrombocytopenia (CRT) and 20 healthy children. We also assessed the effects of intravenous immunoglobulin (IVIG) and methyl prednisolone therapies on the platelet apoptosis in children with newly diagnosed ITP. We demonstrated significantly higher values of caspase 3 in the newly diagnosed ITP group than control and CRT groups, and non-significantly higher values of caspase 8 in the ITP group than the healthy group. After IVIG treatment, the platelet count increased in all patients, and there was a significant decrease in caspase 3 and caspase 8 levels while BCL2 level increased. Regarding methylprednisolone treatment, there was a significant decrease in BCL2 and caspase 8 levels while caspase 3 levels did not significantly decrease. There is a possible role of the caspase dependent cell death pathway of the platelets in the occurrence of newly diagnosed ITP. There is heterogeneity in the apoptotic changes of newly diagnosed ITP children who received IVIG versus those who received methylprednisolone.
Multiple criteria decision making and robust optimization to design a development plan for small and medium-sized enterprises in the east of Iran
Authors: Moazzeni Sahar , Mostafayi Darmian Sobhan , Hvattum Lars Magnus
Published: February 2023

This paper is based on a project of developing small and medium-sized enterprises in South Khorasan, Iran. A combination of multiple criteria decision making and robust multi-objective optimization is used for prioritizing industrial clusters and optimally assigning governmental funds. First, criteria for evaluating clusters are weighted using the best-worst method and clusters are prioritized using the VIKOR method. Second, governmental funding is assigned to the highest priority cluster using robust multi-objective mathematical programming. An innovative method is applied to identify the solution of the Pareto-front with the highest efficiency. In a case study from South Khorasan, computational results show that international market share attraction is the most important criterion and the age of the cluster is the least important criterion in the development of the industrial clusters. The cluster defined for barberry and jujube fruits is determined to be the first-ranked cluster. Most of the total available budget for the development of this cluster is assigned to action plans for marketing and trade development and for investment and financial planning. The proposed methodology thus successfully aided the decision makers to plan their work regarding funding of industrial clusters. We believe that the methodology can be applied as a general tool to help managers of industrial development to better assign governmental funding to develop industrial clusters.
Size- and temperature-dependent oxidative pyrolysis and auto-ignition of spherical beech and spruce wood
Authors: Preimesberger Christoph , Wondrak Maximilian , Solt-Rindler Axel , Pfeifer Christoph , Hansmann Christian
Published: February 2023

Opposed to piloted ignition, where a substance is ignited by an external flame or spark, the term auto-ignition describes the onset of combustion by spontaneous ignition without an external source. In this study, the influence of the size of spherical wood samples and the temperature surrounding the samples was investigated by performing ignition experiments in a muffle furnace with beech and spruce wood. On a specially constructed rig, spheres with four different diameters (8 mm, 12 mm, 18 mm, and 25 mm) were put into a preheated furnace at five isothermal temperatures (240 °C, 270 °C, 300 °C, 330 °C, and 360 °C). For every temperature, diameter, and wood species, the experiments were repeated eight times, and positions of the spheres on the rig were changed for every measurement. Temperatures inside the samples were recorded with thermocouples (TC) positioned in holes drilled to the middle of the spheres. With rising size and temperature, samples were more prone to auto-ignition in a glowing mode, due to a larger, highly reactive pyrolyzed surface and internal overheating. During heating and oxidative pyrolysis, isothermal phases were present at approximately 360 °C in the recorded temperature curves. The comparison to simultaneous thermal analysis (STA) measurements shows decomposition of hemicelluloses, and cellulose is highest around 360 °C. It is concluded that pyrolysis and disintegration of the main wood constituents use up all arising energy. Due to differences in the composition of the wood polymers, beech wood samples already ignite at lower temperatures compared to spruce wood samples with the same diameter. It can be concluded that the size is a critical factor for auto-ignition at the used temperatures. Larger samples will produce more volatile compounds during pyrolysis and have a larger pyrolyzed, porous surface area where heterogenous oxidation reactions can happen. The influence of the size is already critical at differences on the millimetre scale.
The dual of the sequence spaces with mixed norms $$l^{(p, \infty )}$$
Authors: Lang J. , Méndez O.
Published: February 2023

We identify a norm-dense subspace of the dual of the sequence space $$l^{(p,\infty )}$$

l

(
p
,
∞
)

, thus closing the existing gap in the literature. We based our approach on the notion of James orthogonality, absolutely continuous norms and on the uniform convexity and the uniform smoothness of the underlying subspaces.
Fatigue and burst tests of full-scale girth welded pipeline sections for safe operations
Authors: Dakhel A. Y. , Gáspár M. , Koncsik Zs. , Lukács J.
Published: February 2023

The main objective of our ongoing research is data collection for integrity management (IM) tasks, in other words for pipeline integrity management system (PIMS), helping the transporting pipeline operators in different decision situations. Either the reserves of the girth welds after a long-term operation can be identified or the girth welds with different defects should be repaired and/or replaced. From the operators’ point of view, the long-term operation is the cost-effective way; however, from the safety point of view, the managing of the lifecycle of the pipeline is the more reliable way. Unfortunately, inadequate girth welds cause catastrophic damages in transporting pipelines, all over the world. Consequently, the optimal operation of the pipelines is a complex task. The paper introduces our investigation program executed on full-scale pipeline sections. Fatigue (100,000 cycles) and burst tests were executed on different pipeline sections containing girth welds. Long-term operated and replaced gas transporting pipeline sections, furthermore, both appropriate and inadequate girth welds were investigated. The testing results and the damage histories were compared with each other; safety factor (SF) was defined and calculated for the assessment of the reliability of the girth welds.
Multi-criteria decision-making of manufacturing resources allocation for complex product system based on intuitionistic fuzzy information entropy and TOPSIS
Authors: Luo Xu , Guo Shunsheng , Du Baigang , Guo Jun , Jiang Peng , Tan Tian
Published: February 2023

Manufacturing resources allocation (MRA) is important area, and a significant challenge is encountered when considering high value, customized, complex structure and long lifespan of complex product system (CoPS). The relationship between uncertainty factors (i.e., inputs and outputs) of processes in CoPS’s manufacturing, operation and maintenance needs comprehensive trade-offs in the preliminary MRA stage. Meanwhile, the CoPS’s MRA schemes are contradictory from a customer’s perspective with different emphasis on operating cost related to operation and maintenance stage. These problems are unavailable in traditional expressions for model and objective function. In this paper, a new variant of MRA multi-criteria decision-making (MCDM) model of CoPS (MRA&CoPS) is developed to evaluate MRA schemes with considering CoPS’s lifecycle. Meanwhile, considering characteristics of CoPS and customer-involved MRA process, the three-layer criteria cumulative model is established. In the proposed method, intuitionistic fuzzy sets (IFSs) based subjective–objective hybrid fuzzy method is presented to deal with uncertainty of evaluation criteria. The weights of criteria are determined by the proposed intuitionistic fuzzy information entropy (IFIE). The hybrid IFIE-TOPSIS method is proposed to obtain the optimum MRA scheme by ranking results. An example of CoPS’s MRA in a case enterprise is addressed to verify the rationality and validity of the proposed method. The results show that the proposed method is more preferable and robust in MCDM problem of MRA&CoPS.
Relational Aggression in Adolescents Across Different Cultural Contexts: A Systematic Review of the Literature
Authors: Voulgaridou Ioanna , Kokkinos Constantinos M.
Published: February 2023

Relational aggression is defined as harming peers’ relationships through exclusion, rumors, and manipulation. Seminal work on adolescent relational aggression has documented its prevalence across diverse cultural settings. However, efforts to investigate the impact of cultural norms on relational aggression are limited. The purpose of the present review is to present the existing research on relational aggression across cultures during adolescence, a developmental period where the importance of peer relations peaks. Emphasis was placed on gender differences in relational aggression cross-culturally. A systematic literature search between 2010 and 2022 yielded 76 published studies, classified according to studies’ characteristics (participants, information source, study’s design), gender differences and relational aggression’s prevalence. Adolescents in European and American countries reported low scores on relational aggression, while the majority of the studies that were conducted in Asia indicated higher engagement in relational aggression. In Africa and Australia, the findings were inconclusive regarding the prevalence of relational aggression. One third of the studies found non-significant gender differences in adolescent relational aggression. The majority of the studies in Africa, Asia, Australia, and Europe showed that males scored higher on relational aggression, while in America most of the research demonstrated higher scores for females. Future comparative research on relational aggression during adolescence across cultures is suggested.
Empirical likelihood inference for monotone index model
Authors: Otsu Taisuke , Takahata Keisuke , Xu Mengshan
Published: February 2023

This paper proposes an empirical likelihood inference method for monotone index models. We construct the empirical likelihood function based on a modified score function developed by Balabdaoui et al. (Scand J Stat 46:517–544, 2019), where the monotone link function is estimated by isotonic regression. It is shown that the empirical likelihood ratio statistic converges to a weighted chi-squared distribution. We suggest inference procedures based on an adjusted empirical likelihood statistic that is asymptotically pivotal, and a bootstrap calibration with recentering. A simulation study illustrates usefulness of the proposed inference methods.
Anti-Tank Guided Missile System Design Based on an Object Detection Model and a Camera
Authors: Suliman Hamed M. , Kivrak Sinan
Published: February 2023

First-generation anti-tank guided missiles (ATGMs) mainly rely on the skills of operators to guide them in hitting targets, thus making them inaccurate. However, third-generation ATGMs are affected by electronic disruption and are extremely expensive. For example, the accurate range for anti-tank RPGs is 100 m, while the range of the ATGM Javelin is just 4 km (Lightweight CLU) and the cost is US$249,700 (Lightweight CLU only). However, the range of our system depends on the camera range used, which can exceed 50 km on flat ground, and the cost is a few thousand dollars. In this paper, an object detection model was used to recognize a targeted tank, and the fundamental matrix and triangulation approaches were utilized to determine the location of the target tank. Thus, the produced control circuit is smart, autonomous, accurate, with a wide range, and quite inexpensive. The system was installed on an anti-tank missile, tested indoors, and worked correctly. Using object detection models and computer vision technologies in the weapon industry led to the production of an intelligent weapon that is smart, has more range, and is autonomous.
Using Van Allen Probes and Arase Observations to Develop an Empirical Plasma Density Model in the Inner Zone
Authors: Hartley D. P. , Cunningham G. S. , Ripoll J.‐F. , Malaspina D. M. , Kasahara Y. , Miyoshi Y. , Matsuda S. , Nakamura S. , Tsuchiya F. , Kitahara M. , Kumamoto A. , Shinohara I. , Matsuoka A.
Published: February 2023

A new empirical density model is developed for the inner zone between 1 < L < 3 using plasma densities inferred from the upper hybrid resonance on Arase, and hiss‐inferred density values from Van Allen Probes. The Van Allen Probes hiss‐inferred densities are first recalibrated and validated against Arase observations, using both a conjunction event and statistical analyses. The newly developed density model includes dependencies on L, magnetic latitude, and magnetic local time (MLT). Between 1.5 < L < 3.0, the equatorial density variation with L is shown to be equivalent to that of the Ozhogin et al. (2012, https://doi.org/10.1029/2011JA017330) model. However, for L < 1.5, this dependence changes as the plasma density increases at a faster rate with decreasing L. The latitudinal dependence of the plasma density is shown to present a flatter profile than previous models, meaning lower densities extend to higher latitudes. This dependence is well‐modeled by updated fitting coefficients. A clear MLT dependence of the plasma density is identified, which was not found or included in some previous models. This variation is consistent with the diurnal variation of the ionosphere, peaking near MLT = 14 and becoming larger in amplitude with decreasing L. A function describing this MLT dependence is presented. Overall, the new L, latitude, and MLT‐dependent empirical model can provide density values in areas outside the validity region of many previous models, making it a useful resource for accurately determining diffusion coefficients and predicting electron dynamics and their lifetimes in the inner radiation belt.
Bio‐Optical, Physical, and Chemical Properties of a Loop Current Eddy in the Gulf of Mexico
Authors: Zhang Yingjun , Hu Chuanmin , Barnes Brian B. , Liu Yonggang , Kourafalou Vassiliki H. , McGillicuddy Dennis J. , Cannizzaro Jennifer P. , English David C. , Lembke Chad
Published: February 2023

Multi‐sensor data collected with in situ and satellite instruments during August 2015 were used to understand how the three‐dimensional bio‐optical properties of a Loop Current Eddy (LCE) in the Gulf of Mexico (GoM) contrast those of the background waters, and how these properties are related to physical and chemical properties. With a surface radius of ∼150 km and vertical extension to 1,400–1,500 m, the LCE was found to have highly stratified waters in two layers, with one lying just below the mixed layer (16 m) and the other coinciding with the pycnocline (∼120–200 m within the eddy). Strong contrasts were found in the bio‐optical properties (chlorophyll‐a concentration, absorption of particulate and dissolved matters, particulate backscattering, and beam‐c attenuation) across the eddy core, eddy edge, and surrounding waters. Absorption coefficients (400 nm) of surface particulate and dissolved matters were ∼4 times higher in the surrounding waters than in the eddy core, while surface reflectance (400 nm) in the eddy core was ∼7 times higher than in the surrounding waters. The magnitude of deep chlorophyll maximum (DCM) was comparable (0.3–0.33 mg/m3) in all waters, but the depth of DCM in the eddy core (∼115 m) was much deeper than in the surrounding waters (60–75 m). These contrasts were found to correspond to different water masses with different physical (temperature, density, and buoyancy frequency) and chemical properties (salinity and dissolved oxygen concentration), where physical processes (river plume advection and eddy‐induced downwelling) appeared to drive the changes in bio‐optical properties.
A Novel Two‐Step Method for Enforcing Water Budget Closure and an Intercomparison of Budget Closure Correction Methods Based on Satellite Hydrological Products
Authors: Luo Zengliang , Li Huan , Zhang Sihan , Wang Lunche , Wang Shaoqiang , Wang Lizhe
Published: February 2023

Enforcing terrestrial water budget closure is critical for obtaining consistent data sets of budget components to understand the changes and availability of water resources over time. However, most existing budget closure correction methods (BCCs) are significantly affected by errors in the budget‐component products. Moreover, these existing BCCs do not fully account for the preselection of high‐precision input data sets before enforcing the water budget closure, resulting in uncertainties in the budget‐corrected data sets. In this study, a two‐step method was proposed to enforce the water budget closure of satellite‐based hydrological products. First, high‐precision budget‐component data sets were selected and second, the water budget closure of the selected high‐precision data sets was then enforced by proposing an improved BCC strategy, that is, the Minimized Series Deviation method (MSD). The performance of the proposed two‐step method was verified in 24 global basins by comparing it to three existing BCCs of varying complexity, that is, Proportional Redistribution (PR), Constrained Kalman Filter (CKF), and Multiple Collocation (MCL). The results showed that compared to the existing BCCs, the proposed two‐step method significantly improved the accuracy of budget‐corrected data sets in the range of 2%–19% (statistical analysis was based root mean square error (RMSE) and mean absolute error (MAE) with estimated observation (EO) as a reference). This study also summarized the main factors influencing the performance of the existing BCCs and their further development prospects based on the results. This provides insight into the expansion of theories and methods related to closing the terrestrial water budget.
Targeted metabolomics detects a putatively diagnostic signature in plasma and dried blood spots from head and neck paraganglioma patients
Authors: De Fabritiis Simone , Valentinuzzi Silvia , Piras Gianluca , Cicalini Ilaria , Pieragostino Damiana , Pagotto Sara , Perconti Silvia , Zucchelli Mirco , Schena Alberto , Taschin Elisa , Berteşteanu Gloria Simona , Esposito Diana Liberata , Stigliano Antonio , De Laurenzi Vincenzo , Schiavi Francesca , Sanna Mario , Del Boccio Piero , Verginelli Fabio , Mariani-Costantini Renato
Published: February 2023

Head and neck paragangliomas (HNPGLs), rare chemoresistant tumors curable only with surgery, are strongly influenced by genetic predisposition, hence patients and relatives require lifetime follow-up with MRI and/or PET-CT because of de novo disease risk. This entails exposure to electromagnetic/ionizing radiation, costs, and organizational challenges, because patients and relatives are scattered far from reference centers. Simplified first-line screening strategies are needed. We employed flow injection analysis tandem mass spectrometry, as used in newborn metabolic screening, to compare the plasma metabolic profile of HNPGL patients (59 samples, 56 cases) and healthy controls (24 samples, 24 cases). Principal Component Analysis (PCA) and Partial Least Discriminant Analysis (PLS-DA) highlighted a distinctive HNPGL signature, likely reflecting the anaplerotic conversion of the TCA cycle to glutaminolysis and catabolism of branched amino acids, DNA damage and deoxyadenosine (dAdo) accumulation, impairment of fatty acid oxidation, switch towards the Warburg effect and proinflammatory lysophosphatidylcholines (LPCs) signaling. Statistical analysis of the metabolites that most impacted on PLS-DA was extended to 10 acoustic neuroma and 2 cholesteatoma patients, confirming significant differences relative to the HNPGL plasma metabolomic profile. The best confusion matrix from the ROC curve built on 2 metabolites, dAdo and C26:0-LPC, provided specificity of 94.29% and sensitivity of 89.29%, with positive and negative predictive values of 96.2% and 84.6%, respectively. Analysis of dAdo and C26:0-LPC levels in dried venous and capillary blood confirmed that dAdo, likely deriving from 2′-deoxy-ATP accumulated in HNPGL cells following endogenous genotoxic damage, efficiently discriminated HNPGL patients from healthy controls and acoustic neuroma/cholesteatoma patients on easily manageable dried blood spots.
PELI1 and EGFR cooperate to promote breast cancer metastasis
Authors: Qi Jie , Xu Guangsen , Wu Xiaoxia , Lu Chunhua , Shen Yuemao , Zhao Baobing
Published: February 2023

Pellino-1 (PELI1) is an E3 ubiquitin ligase acting as a key regulator for the inflammation and autoimmunity via the ubiquitination of the substrate proteins. There is increasing evidence to support that PELI1 functions as an oncoprotein in tumorigenesis and metastasis. However, the molecular mechanism underlying the high expression and oncogenic roles of PELI1 in cancers remains limited. Herein, we revealed a novel regulation mechanism by which PELI1 and EGFR cooperate to promote breast cancer metastasis. EGFR is positively correlated with PELI1 expression in breast cancers, and its activation led to the phosphorylation of PELI1 at Tyr154 and Thr264, which subsequently activated its E3 ubiquitin ligase. Simultaneously, PELI1 physically interacted with and enhanced the stability of EGFR via the K63-linked polyubiquitination in reverse. The co-inhibition of the PELI1-EGFR showed synergetic effect to repress breast cancer metastasis. Furthermore, we identified a compound S62 as a small molecule disruptor of PELI1/EGFR that effectively repressed breast cancer metastasis. Our study not only uncovered the emerging roles of PELI1/EGFR interaction in the progression of breast cancer, but also provided an effective strategy for the inhibition of metastasis in breast cancer.
Sestrin2: multifaceted functions, molecular basis, and its implications in liver diseases
Authors: Lu Chunfeng , Jiang Yiming , Xu Wenxuan , Bao Xiaofeng
Published: February 2023

Sestrin2 (SESN2), a highly conserved stress-responsive protein, can be triggered by various noxious stimuli, such as hypoxia, DNA damage, oxidative stress, endoplasmic reticulum (ER) stress, and inflammation. Multiple transcription factors regulate SESN2 expression, including hypoxia-inducible factor 1 (HIF-1), p53, nuclear factor E2-related factor 2 (Nrf2), activating transcription factor 4 (ATF4), ATF6, etc. Upon induction, SESN2 generally leads to activation of adenosine monophosphate-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin complex 1 (mTORC1). To maintain cellular homeostasis, SESN2 and its downstream molecules directly scavenge reactive oxygen species or indirectly influence the expression patterns of key genes associated with redox, macroautophagy, mitophagy, ER stress, apoptosis, protein synthesis, and inflammation. In liver diseases including acute liver injury, fatty liver diseases, hepatic fibrosis, and hepatocellular carcinoma (HCC), SESN2 is abnormally expressed and correlated with disease progression. In NAFLD, SESN2 helps with postponing disease progression through balancing glycolipid metabolism and macroautophagy (lipophagy), and rectifying oxidative damage and ER stress. During hepatic fibrosis, SESN2 represses HSCs activation and intrahepatic inflammation, hindering the occurrence and progress of fibrogenesis. However, the role of SESN2 in HCC is controversial due to its paradoxical pro-autophagic and anti-apoptotic effects. In conclusion, this review summarizes the biological functions of SESN2 in hypoxia, genotoxic stress, oxidative stress, ER stress, and inflammation, and specifically emphasizes the pathophysiological significance of SESN2 in liver diseases, aiming to providing a comprehensive understanding for SESN2 as a potential therapeutic target in liver diseases.
DAPL1 prevents epithelial–mesenchymal transition in the retinal pigment epithelium and experimental proliferative vitreoretinopathy
Authors: Ma Xiaoyin , Han Shuxian , Liu Youjia , Chen Yu , Li Pingping , Liu Xiaoyan , Chang Lifu , Chen Ying-ao , Chen Feng , Hou Qiang , Hou Ling
Published: February 2023

Epithelial–mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is a hallmark of the pathogenesis of proliferative vitreoretinopathy (PVR) that can lead to severe vision loss. Nevertheless, the precise regulatory mechanisms underlying the pathogenesis of PVR remain largely unknown. Here, we show that the expression of death-associated protein-like 1 (DAPL1) is downregulated in PVR membranes and that DAPL1 deficiency promotes EMT in RPE cells in mice. In fact, adeno-associated virus (AAV)-mediated DAPL1 overexpression in RPE cells of Dapl1-deficient mice inhibited EMT in physiological and retinal-detachment states. In a rabbit model of PVR, ARPE-19 cells overexpressing DAPL1 showed reduced ability to induce experimental PVR, and AAV-mediated DAPL1 delivery attenuated the severity of experimental PVR. Furthermore, a mechanistic study revealed that DAPL1 promotes P21 phosphorylation and its stabilization partially through NFκB (RelA) in RPE cells, whereas the knockdown of P21 led to neutralizing effects on DAPL1-dependent EMT inhibition and enhanced the severity of experimental PVR. These results suggest that DAPL1 acts as a novel suppressor of RPE-EMT and has an important role in antagonizing the pathogenesis of experimental PVR. Hence, this finding has implications for understanding the mechanism of and potential therapeutic applications for PVR.
Structural consequences of turnover-induced homocitrate loss in nitrogenase
Authors: Warmack Rebeccah A. , Maggiolo Ailiena O. , Orta Andres , Wenke Belinda B. , Howard James B. , Rees Douglas C.
Published: February 2023

Nitrogenase catalyzes the ATP-dependent reduction of dinitrogen to ammonia during the process of biological nitrogen fixation that is essential for sustaining life. The active site FeMo-cofactor contains a [7Fe:1Mo:9S:1C] metallocluster coordinated with an R-homocitrate (HCA) molecule. Here, we establish through single particle cryoEM and chemical analysis of two forms of the Azotobacter vinelandii MoFe-protein – a high pH turnover inactivated species and a ∆NifV variant that cannot synthesize HCA – that loss of HCA is coupled to α-subunit domain and FeMo-cofactor disordering, and formation of a histidine coordination site. We further find a population of the ∆NifV variant complexed to an endogenous protein identified through structural and proteomic approaches as the uncharacterized protein NafT. Recognition by endogenous NafT demonstrates the physiological relevance of the HCA-compromised form, perhaps for cofactor insertion or repair. Our results point towards a dynamic active site in which HCA plays a role in enabling nitrogenase catalysis by facilitating activation of the FeMo-cofactor from a relatively stable form to a state capable of reducing dinitrogen under ambient conditions.
The translating bacterial ribosome at 1.55 Å resolution generated by cryo-EM imaging services
Authors: Fromm Simon A. , O’Connor Kate M. , Purdy Michael , Bhatt Pramod R. , Loughran Gary , Atkins John F. , Jomaa Ahmad , Mattei Simone
Published: February 2023

Our understanding of protein synthesis has been conceptualised around the structure and function of the bacterial ribosome. This complex macromolecular machine is the target of important antimicrobial drugs, an integral line of defence against infectious diseases. Here, we describe how open access to cryo-electron microscopy facilities combined with bespoke user support enabled structural determination of the translating ribosome from Escherichia coli at 1.55 Å resolution. The obtained structures allow for direct determination of the rRNA sequence to identify ribosome polymorphism sites in the E. coli strain used in this study and enable interpretation of the ribosomal active and peripheral sites at unprecedented resolution. This includes scarcely populated chimeric hybrid states of the ribosome engaged in several tRNA translocation steps resolved at ~2 Å resolution. The current map not only improves our understanding of protein synthesis but also allows for more precise structure-based drug design of antibiotics to tackle rising bacterial resistance.
Single-cell quantification and dose-response of cytosolic siRNA delivery
Authors: Hedlund Hampus , Du Rietz Hampus , Johansson Johanna M. , Eriksson Hanna C. , Zedan Wahed , Huang Linfeng , Wallin Jonas , Wittrup Anders
Published: February 2023

Endosomal escape and subsequent cytosolic delivery of small interfering RNA (siRNA) therapeutics is believed to be highly inefficient. Since it has not been possible to quantify cytosolic amounts of delivered siRNA at therapeutic doses, determining delivery bottlenecks and total efficiency has been difficult. Here, we present a confocal microscopy-based method to quantify cytosolic delivery of fluorescently labeled siRNA during lipid-mediated delivery. This method enables detection and quantification of sub-nanomolar cytosolic siRNA release amounts from individual release events with measures of quantitation confidence for each event. Single-cell kinetics of siRNA-mediated knockdown in cells expressing destabilized eGFP unveiled a dose-response relationship with respect to knockdown induction, depth and duration in the range from several hundred to thousands of cytosolic siRNA molecules. Accurate quantification of cytosolic siRNA, and the establishment of the intracellular dose-response relationships, will aid the development and characterization of novel delivery strategies for nucleic acid therapeutics.
Evidence of ghost plagioclase signature induced by kinetic fractionation of europium in the Earth’s mantle
Authors: Tilhac Romain , Hidas Károly , Oliveira Beñat , Garrido Carlos J.
Published: February 2023

Crustal recycling in the Earth’s mantle is fingerprinted by trace-element and isotopic proxies in oceanic basalts. Positive Eu and Sr anomalies in primitive lavas and melt inclusions that are not otherwise enriched in Al2O3are often interpreted as reflecting the presence of recycled, plagioclase-rich oceanic crust in their mantle source – referred to as “ghost plagioclase” signatures. Here, we report natural evidence of Eu anomalies and extreme crystal-scale heterogeneity developed kinetically in mantle peridotite clinopyroxene. Numerical modelling shows that diffusional fractionation between clinopyroxene and melts can account for this intra-crystal heterogeneity and generate Eu anomalies without requiring plagioclase. We demonstrate that kinetically induced Eu anomalies are likely to develop at temperatures, redox conditions and transport timescales compatible with the genesis of mid-ocean ridge and ocean island basalts. Our results show that, in the absence of converging lines of evidence such as radiogenic isotope data, ghost plagioclase signatures are not an unequivocal proxy for the presence of recycled crust in oceanic basalt sources.
Stress-induced plasticity of a CRH/GABA projection disrupts reward behaviors in mice
Authors: Birnie Matthew T. , Short Annabel K. , de Carvalho Gregory B. , Taniguchi Lara , Gunn Benjamin G. , Pham Aidan L. , Itoga Christy A. , Xu Xiangmin , Chen Lulu Y. , Mahler Stephen V. , Chen Yuncai , Baram Tallie Z.
Published: February 2023

Disrupted operations of the reward circuit underlie major emotional disorders, including depression, which commonly arise following early life stress / adversity (ELA). However, how ELA enduringly impacts reward circuit functions remains unclear. We characterize a stress-sensitive projection connecting basolateral amygdala (BLA) and nucleus accumbens (NAc) that co-expresses GABA and the stress-reactive neuropeptide corticotropin-releasing hormone (CRH). We identify a crucial role for this projection in executing disrupted reward behaviors provoked by ELA: chemogenetic and optogenetic stimulation of the projection in control male mice suppresses several reward behaviors, recapitulating deficits resulting from ELA and demonstrating the pathway’s contributions to normal reward behaviors. In adult ELA mice, inhibiting–but not stimulating–the projection, restores typical reward behaviors yet has little effect in controls, indicating ELA-induced maladaptive plasticity of this reward-circuit component. Thus, we discover a stress-sensitive, reward inhibiting BLA → NAc projection with unique molecular features, which may provide intervention targets for disabling mental illnesses.
Bright Tm3+-based downshifting luminescence nanoprobe operating around 1800 nm for NIR-IIb and c bioimaging
Authors: Chang Yulei , Chen Haoren , Xie Xiaoyu , Wan Yong , Li Qiqing , Wu Fengxia , Yang Run , Wang Wang , Kong Xianggui
Published: February 2023

Fluorescence bioimaging based on rare-earth-doped nanocrystals (RENCs) in the shortwave infrared (SWIR, 1000–3000 nm) region has aroused intense interest due to deeper penetration depth and clarity. However, their downshifting emission rarely shows sufficient brightness beyond 1600 nm, especially in NIR-IIc. Here, we present a class of thulium (Tm) self-sensitized RENC fluorescence probes that exhibit bright downshifting luminescence at 1600–2100 nm (NIR-IIb/c) for in vivo bioimaging. An inert shell coating minimizes surface quenching and combines strong cross-relaxation, allowing LiTmF4@LiYF4 NPs to emit these intense downshifting emissions by absorbing NIR photons at 800 nm (large Stokes shift ~1000 nm with a absolute quantum yield of ~14.16%) or 1208 nm (NIR-IIin and NIR-IIout). Furthermore, doping with Er3+ for energy trapping achieves four-wavelength NIR irradiation and bright NIR-IIb/c emission. Our results show that Tm-based NPs, as NIR-IIb/c nanoprobes with high signal-to-background ratio and clarity, open new opportunities for future applications and translation into diverse fields.
Biomineralization-inspired mineralized hydrogel promotes the repair and regeneration of dentin/bone hard tissue
Authors: Wen Bo , Dai Yuguo , Han Xue , Huo Fangjun , Xie Li , Yu Mei , Wang Yuru , An Ning , Li Zhonghan , Guo Weihua
Published: February 2023

Maxillofacial hard tissue defects caused by trauma or infection often affect craniofacial function. Taking the natural hard tissue structure as a template, constructing an engineered tissue repair module is an important scheme to realize the functional regeneration and repair of maxillofacial hard tissue. Here, inspired by the biomineralization process, we constructed a composite mineral matrix hydrogel PAA-CMC-TDM containing amorphous calcium phosphates (ACPs), polyacrylic acid (PAA), carboxymethyl chitosan (CMC) and dentin matrix (TDM). The dynamic network composed of Ca2+·COO− coordination and ACPs made the hydrogel loaded with TDM, and exhibited self-repairing ability and injectability. The mechanical properties of PAA-CMC-TDM can be regulated, but the functional activity of TDM remains unaffected. Cytological studies and animal models of hard tissue defects show that the hydrogel can promote the odontogenesis or osteogenic differentiation of mesenchymal stem cells, adapt to irregular hard tissue defects, and promote in situ regeneration of defective tooth and bone tissues. In summary, this paper shows that the injectable TDM hydrogel based on biomimetic mineralization theory can induce hard tissue formation and promote dentin/bone regeneration.
Variational quantum approximate support vector machine with inference transfer
Authors: Park Siheon , Park Daniel K. , Rhee June-Koo Kevin
Published: February 2023

A kernel-based quantum classifier is the most practical and influential quantum machine learning technique for the hyper-linear classification of complex data. We propose a Variational Quantum Approximate Support Vector Machine (VQASVM) algorithm that demonstrates empirical sub-quadratic run-time complexity with quantum operations feasible even in NISQ computers. We experimented our algorithm with toy example dataset on cloud-based NISQ machines as a proof of concept. We also numerically investigated its performance on the standard Iris flower and MNIST datasets to confirm the practicality and scalability.
On the potential of transauricular electrical stimulation to reduce visually induced motion sickness
Authors: Molefi Emmanuel , McLoughlin Ian , Palaniappan Ramaswamy
Published: February 2023

Perturbations in the autonomic nervous system occur in individuals experiencing increasing levels of motion sickness. Here, we investigated the effects of transauricular electrical stimulation (tES) on autonomic function during visually induced motion sickness, through the analysis of spectral and time-frequency heart rate variability. To determine the efficacy of tES, we compared sham and tES conditions in a randomized, within-subjects, cross-over design in 14 healthy participants. We found that tES reduced motion sickness symptoms by significantly increasing normalized high-frequency (HF) power and decreasing both normalized low-frequency (LF) power and the power ratio of LF and HF components (LF/HF ratio). Furthermore, behavioral data recorded using the motion sickness assessment questionnaire (MSAQ) showed significant differences in decreased symptoms during tES compared to sham condition for the total MSAQ scores and, central and sopite categories of the MSAQ. Our preliminary findings suggest that by administering tES, parasympathetic modulation is increased, and autonomic imbalance induced by motion sickness is restored. This study provides first evidence that tES may have potential as a non-pharmacological neuromodulation tool to keep motion sickness at bay. Thus, these findings may have implications towards protecting people from becoming motion sick and possible accelerated recovery from the malady.