bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of Fluorescent Aptasensors Based on G-Quadruplex Quenching Ability for Ochratoxin A and Potassium Ions Detection
Authors: Yang Cheng , Chu Xiaolin , Zeng Li , Rhouati Amina , Abbas Fathimath , Cui Shengnan , Lin Daiqin
Published: June 2022

G-quadruplexes have received significant attention in aptasensing due to their structural polymorphisms and unique binding properties. In this work, we exploited the fluorescence-quenching properties of G-quadruplex to develop a simple, fast, and sensitive platform for fluorescence detection of ochratoxin A (OTA) and potassium ions (K+) with a label-free fluorophore and quencher strategy. The quenching ability of G-quadruplex was confirmed during the recognition process after the formation of the G-quadruplex structure and the quenching of the labeled fluorescein fluorophore (FAM). The fluorescence-quenching mechanism was studied by introducing specific ligands of G-quadruplex to enhance the quenching effect, to show that this phenomenon is due to photo-induced electron transfer. The proposed fluorescence sensor based on G-quadruplex quenching showed excellent selectivity with a low detection limit of 0.19 nM and 0.24 µM for OTA and K+, respectively. Moreover, we demonstrated that our detection method enables accurate concentration determination of real samples with the prospect of practical application. Therefore, G-quadruplexes can be excellent candidates as quenchers, and the strategy implemented in the study can be extended to an aptasensor with G-quadruplex.
Autism Spectrum Disorder and Fetal Alcohol Spectrum Disorder: A Literature Review
Authors: Carpita Barbara , Migli Lavinia , Chiarantini Ilaria , Battaglini Simone , Montalbano Clara , Carmassi Claudia , Cremone Ivan Mirko , Dell’Osso Liliana
Published: June 2022

Fetal alcohol spectrum disorders (FASD) are a group of conditions associated with the effects of prenatal alcohol exposure and characterized by somatic and neuropsychological alterations. On the other hand, autism spectrum disorder (ASD) is characterized by a multifaceted neurobehavioral syndrome. Since alcohol can affect every stage of brain development, some authors hypothesized that in utero alcohol exposure might be linked to an increased risk of ASD in subjects with genetic vulnerability. The present review aimed to summarize the available literature on the possible association between FASD and ASD, also focusing on the reported clinical overlaps and on the possible shared pathogenic mechanisms. Studies in this field have stressed similarities and differences between the two conditions, leading to controversial results. The available literature also highlighted that both the disorders are often misdiagnosed or underdiagnosed, stressing the need to broaden the perspective, paying specific attention to milder presentations and sub-syndromic traits.
Binge-like Prenatal Ethanol Exposure Causes Impaired Cellular Differentiation in the Embryonic Forebrain and Synaptic and Behavioral Defects in Adult Mice
Authors: Subbanna Shivakumar , Basavarajappa Balapal S.
Published: June 2022

An embryo’s in-utero exposure to ethanol due to a mother’s alcohol drinking results in a range of deficits in the child that are collectively termed fetal alcohol spectrum disorders (FASDs). Prenatal ethanol exposure is one of the leading causes of preventable intellectual disability. Its neurobehavioral underpinnings warrant systematic research. We investigated the immediate effects on embryos of acute prenatal ethanol exposure during gestational days (GDs) and the influence of such exposure on persistent neurobehavioral deficits in adult offspring. We administered pregnant C57BL/6J mice with ethanol (1.75 g/kg) (GDE) or saline (GDS) intraperitoneally (i.p.) at 0 h and again at 2 h intervals on GD 8 and GD 12. Subsequently, we assessed apoptosis, differentiation, and signaling events in embryo forebrains (E13.5; GD13.5). Long-lasting effects of GDE were evaluated via a behavioral test battery. We also determined the long-term potentiation and synaptic plasticity-related protein expression in adult hippocampal tissue. GDE caused apoptosis, inhibited differentiation, and reduced pERK and pCREB signaling and the expression of transcription factors Pax6 and Lhx2. GDE caused persistent spatial and social investigation memory deficits compared with saline controls, regardless of sex. Interestingly, GDE adult mice exhibited enhanced repetitive and anxiety-like behavior, irrespective of sex. GDE reduced synaptic plasticity-related protein expression and caused hippocampal synaptic plasticity (LTP and LTD) deficits in adult offspring. These findings demonstrate that binge-like ethanol exposure at the GD8 and GD12 developmental stages causes defects in pERK–pCREB signaling and reduces the expression of Pax6 and Lhx2, leading to impaired cellular differentiation during the embryonic stage. In the adult stage, binge-like ethanol exposure caused persistent synaptic and behavioral abnormalities in adult mice. Furthermore, the findings suggest that combining ethanol exposure at two sensitive stages (GD8 and GD12) causes deficits in synaptic plasticity-associated proteins (Arc, Egr1, Fgf1, GluR1, and GluN1), leading to persistent FASD-like neurobehavioral deficits in mice.
Rich Get Richer: Extraversion Statistically Predicts Reduced Internet Addiction through Less Online Anonymity Preference and Extraversion Compensation
Authors: Zhang Shaozhen , Su Wenliang , Han Xiaoli , Potenza Marc N.
Published: June 2022

Internet addiction may arise from multiple factors and personality tendencies have been previously implicated. Prior studies have found that extraversion may be a protective factor mitigating against internet addiction, yielding a “rich-get-richer” effect. However, few studies have explored how extraversion may influence internet addiction from the perspective of online-offline integration. Drawing on a sample of 428 college students, the current study examined a serial mediation model exploring the underlying mechanisms of how extraversion may statistically predict internet addiction through online-offline integration and antecedent factors. The serial mediation model analyses indicated that extraverted internet users exhibited a weaker preference for online anonymity and less online extraversion compensation, thus formulating a higher level of online-offline integration than introverted individuals, which, in turn, appeared to reduce the risk of internet addiction. In contrast, with regard to specific components of online-offline integration, introverted internet users preferred online anonymity, which reduced their relationship integration and increased their likelihood of internet addiction; similarly, the introverted individuals were also more likely to exhibit an extraversion compensation effect. That is, they were more extraverted on the internet than in general; hence, they had a lower level of self-identity integration, resulting in a greater likelihood of experiencing internet addiction. These results highlight the importance of online-offline integration that may account for personality variations in social and psychological outcomes related to internet use, and suggest a role for online anonymity preference and extraversion compensation in influencing specific components of integration.
Predicting Construction Workers’ Intentions to Engage in Unsafe Behaviours Using Machine Learning Algorithms and Taxonomy of Personality
Authors: Gao Yifan , González Vicente A. , Yiu Tak Wing , Cabrera-Guerrero Guillermo , Deng Ruiqi
Published: June 2022

Dynamic environmental circumstances can sometimes be incompatible with proactive human intentions of being safe, leading individuals to take unintended risks. Behaviour predictions, as performed in previous studies, are found to involve environmental circumstances as predictors, which might thereby result in biased safety conclusions about individuals’ inner intentions to engage in unsafe behaviours. This research calls attention to relatively less-understood worker intentions and provides a machine learning (ML) approach to help understand workers’ intentions to engage in unsafe behaviours based on the workers’ inner drives, i.e., personality. Personality is consistent across circumstances and allows insight into one’s intentions. To mathematically develop the approach, data on personality and behavioural intentions was collected from 268 workers. Five ML architectures—backpropagation neural network (BP-NN), decision tree, support vector machine, k-nearest neighbours, and multivariate linear regression—were used to capture the predictive relationship. The results showed that BP-NN outperformed other algorithms, yielding minimal prediction loss, and was determined to be the best approach. The approach can generate quantifiable predictions to understand the extent of workers’ inner intentions to engage in unsafe behaviours. Such knowledge is useful for understanding undesirable aspects in different workers in order to recommend suitable preventive strategies for workers with different needs.
Development of Exclusive Seismic Fragility Curves for Critical Infrastructure: An Oil Pumping Station Case Study
Authors: Urlainis Alon , Shohet Igal
Published: June 2022

Fragility curves are a common tool to appraise the expected damage to critical infrastructure (CI) after an earthquake event. Previous studies offer fragility curve parameters for CI that are suitable for a vast range of systems, without an in-depth examination of the system architecture and subcomponents. These curves are applicable in cases where a thorough analysis is not required or when the information related to a single system is poor. This paper proposes an original approach and presents a comprehensive methodology for developing exclusive fragility curves for critical infrastructure systems. In the proposed methodology, the fragility curves are developed by a decomposition of the system into its main subcomponents and determination of the failure mechanisms. The derivation of the fragility parameters includes failure analysis for each damage state by a Fault Tree Analysis and approximation of the fragility parameters in accordance with the rate of exceedance. The implementation of the methodology is demonstrated by a case study with three alternatives of an oil pumping plant configuration. It was found that a change of a subcomponent has an effect on the derived values of the fragility parameters. Moreover, the variances in the fragility parameters have implications for the effectiveness of each alternative to resist different levels of severity.
Application of Nondestructive Testing Technology in Quality Evaluation of Plain Concrete and RC Structures in Bridge Engineering: A Review
Authors: Zheng Yuanxun , Wang Shaoqiang , Zhang Peng , Xu Tongxin , Zhuo Jingbo
Published: June 2022

The development and application of nondestructive testing technology for prestressed reinforced concrete structures in the field of infrastructure construction were summarized in this study via the analysis of relevant literature worldwide. The detection methods, detection principles, and detection instruments in quality evaluation of prestressed reinforced concrete structures were analyzed and compared, based on which, acoustic emission detection technology, impact echo detection technology, ultrasonic detection technology, infrared thermography detection technology, ground-penetrating radar detection technology, piezoelectric transducer detection technology, and X-ray detection technology were summarized. Additionally, the advantages, disadvantages, and application scope of each detection method were focused upon and analyzed comparatively. It is indicated that further improvement in the detection visualization, accuracy, and efficiency for most nondestructive testing technologies is available by optimizing the algorithm and combining artificial intelligence technology with neural network deep learning, precise positioning, and imaging analysis of the quality defects in prestressed reinforced concrete structures. The results of this study can provide technical reference for the further application and research of nondestructive testing technologies in the quality inspection of prestressed reinforced concrete structures.
Design and Experimental Analysis of Connections for a Panelized Wood Frame Roof System
Authors: Islam Md , Chui Ying , Altaf Mohammed
Published: June 2022

This paper presents the results of an experimental study on the short-term mechanical performance of timber screw connections comprising two types of fasteners suitable for a novel panelized roof design process. Thirty-seven specimens of five different connection configurations were tested under quasi-static monotonic loading. The main objective of this study is to provide a preliminary assessment of connection capacity that is key to the successful implementation of a proposed panelized roof design method. It also provides the basis to assist in the development of a numerical model of the novel roof assembly. Additionally, the experimental data are used to check the validity of existing analytical approaches for predicting the strengths of screwed connections comprising engineered wood members. The validation exercise shows that available analytical models can be used to predict the connection capacity of the novel panelized roof.
Experimental and Numerical Study on Rapid Evacuation Characteristics of Staircases in Campus Buildings
Authors: Zhang Qian , Yu Fei , Gao Shan , Chang Chen , Zhang Xusheng
Published: June 2022

In this work, we conducted downward evacuation experiments in four types of staircases under various smoke visibility conditions of the naked eye, wearing sunglass and wearing eyeshades. Ten male and ten female college students were recruited to conduct the evacuation as a single male, single female, two males supporting one another, two females supporting one another and one male carrying another on his back. The evacuation time on each floor was recorded. The corresponding evacuation models were established by Pathfinder and verified against the test data. The effects of evacuation crowd density and response time considering gender factors on the evacuation time were simulated using the models. The results show that under the experimental condition of low visibility, the curve of evacuation time presents a stable state, whose change with the increase in the floors is not obvious. The increase in the evacuation time under different visibility indicates that males have better adaptability to the environment than females. The curves of SSP (straight running stairs with platform) and DSS (double split parallel stairs) are smoother than those of DPS (double running parallel stairs) and CS (corner stairs), indicating less pressure and less congestion during evacuation. During the emergency evacuation, the crowd pressure on the platform of the staircases is small. The front section of the flight and the corner part of the staircases are prone to congestion during evacuation. Under the influence of gender factors, since the response time of males is longer than that of females, the smaller the proportion of males, the smaller the time growth rate considering the reaction time. With the increase in crowd density, the effect of response time on total evacuation time becomes smaller.
The Promise of Circulating Tumor DNA in Head and Neck Cancer
Authors: Aulakh Sukhkaran S. , Silverman Dustin A. , Young Kurtis , Dennis Steven K. , Birkeland Andrew C.
Published: June 2022

As the seventh most common cancer globally, head and neck cancers (HNC) exert considerable disease burden, with an estimated 277,597 deaths worldwide in 2020 alone. Traditional risk factors for HNC include tobacco, alcohol, and betel nut; more recently, human papillomavirus has emerged as a distinct driver of disease. Currently, limitations of cancer screening and surveillance methods often lead to identifying HNC in more advanced stages, with associated poor outcomes. Liquid biopsies, in particular circulating tumor DNA (ctDNA), offer the potential for enhancing screening, early diagnosis, and surveillance in HNC patients, with potential improvements in HNC patient outcomes. In this review, we examine current methodologies for detecting ctDNA and highlight current research illustrating viral and non-viral ctDNA biomarker utilities in HNC screening, diagnosis, treatment response, and prognosis. We also summarize current challenges and future directions for ctDNA testing in HNC patients.
Validation of a Patient-Derived Xenograft Model for Cervical Cancer Based on Genomic and Phenotypic Characterization
Authors: Miyamoto Shunsuke , Tanaka Tomohito , Hirosuna Kensuke , Nishie Ruri , Ueda Shoko , Hashida Sousuke , Terada Shinichi , Konishi Hiromi , Kogata Yuhei , Taniguchi Kohei , Komura Kazumasa , Ohmichi Masahide
Published: June 2022

Patient-derived xenograft (PDX) models are useful tools for preclinical drug evaluation, biomarker identification, and personalized medicine strategies, and can be developed by the heterotopic or orthotopic grafting of surgically resected tumors into immunodeficient mice. We report the PDX models of cervical cancer and demonstrate the similarities among original and different generations of PDX tumors. Fresh tumor tissues collected from 22 patients with primary cervical cancer were engrafted subcutaneously into NOD.CB17-PrkdcSCID/J mice. Histological and immunohistochemical analyses were performed to compare primary and different generations of PDX tumors. DNA and RNA sequencing were performed to verify the similarity between the genetic profiles of primary and PDX tumors. Total RNA in extracellular vesicles (EVs) released from primary and PDX tumors was also quantified to evaluate gene expression. The total tumor engraftment rate was 50%. Histologically, no major differences were observed between the original and PDX tumors. Most of the gene mutations and expression patterns related to carcinogenesis and infiltration were similar between the primary tumor and xenograft. Most genes associated with carcinogenesis and infiltration showed similar expression levels in the primary tumor and xenograft EVs. Therefore, compared with primary tumors, PDX models could be potentially more useful for translational research.
Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics
Authors: Taiarol Lorenzo , Bigogno Chiara , Sesana Silvia , Kravicz Marcelo , Viale Francesca , Pozzi Eleonora , Monza Laura , Carozzi Valentina Alda , Meregalli Cristina , Valtorta Silvia , Moresco Rosa Maria , Koch Marcus , Barbugian Federica , Russo Laura , Dondio Giulio , Steinkühler Christian , Re Francesca
Published: June 2022

Glioblastoma is the most common and aggressive brain tumor, associated with poor prognosis and survival, representing a challenging medical issue for neurooncologists. Dysregulation of histone-modifying enzymes (HDACs) is commonly identified in many tumors and has been linked to cancer proliferation, changes in metabolism, and drug resistance. These findings led to the development of HDAC inhibitors, which are limited by their narrow therapeutic index. In this work, we provide the proof of concept for a delivery system that can improve the in vivo half-life and increase the brain delivery of Givinostat, a pan-HDAC inhibitor. Here, 150-nm-sized liposomes composed of cholesterol and sphingomyelin with or without surface decoration with mApoE peptide, inhibited human glioblastoma cell growth in 2D and 3D models by inducing a time- and dose-dependent reduction in cell viability, reduction in the receptors involved in cholesterol metabolism (from −25% to −75% of protein levels), and reduction in HDAC activity (−25% within 30 min). In addition, liposome-Givinostat formulations showed a 2.5-fold increase in the drug half-life in the bloodstream and a 6-fold increase in the amount of drug entering the brain in healthy mice, without any signs of overt toxicity. These features make liposomes loaded with Givinostat valuable as potential candidates for glioblastoma therapy.
Unraveling Desmoid-Type Fibromatosis-Specific Health-Related Quality of Life: Who Is at Risk for Poor Outcomes
Authors: Schut Anne-Rose W. , Lidington Emma , Timbergen Milea J. M. , Younger Eugenie , van der Graaf Winette T. A. , van Houdt Winan J. , Bonenkamp Johannes J. , Jones Robin L. , Grünhagen Dirk. J. , Sleijfer Stefan , Verhoef Cornelis , Gennatas Spyridon , Husson Olga
Published: June 2022

Desmoid-type fibromatosis (DTF) is a rare, soft-tissue tumour. These tumours do not metastasize, but their local aggressive tumour growth and unpredictable behaviour can have a significant impact on health-related quality of life (HRQoL). Little is known about which DTF patients are particularly affected by an impaired HRQoL. The objectives of this study were to assess HRQoL among different groups of DTF patients and to investigate which socio-demographic and clinical characteristics were associated with DTF-specific HRQoL. A cross-sectional study was conducted among DTF patients from the United Kingdom and the Netherlands. HRQoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), accompanied by the DTF-QoL to assess DTF-specific HRQoL. The scores were compared amongst subgroups, based on the socio-demographic and clinical characteristics of DTF patients. Multiple linear regression analyses with a backward elimination were conducted to identify the factors associated with DTF-specific HRQoL. A total of 235 DTF patients completed the questionnaires. Female patients, patients with more than two comorbidities, or patients who received treatment other than only active surveillance (AS) or surgery scored significantly worse on the subscales of both the EORTC QLQ-C30 and DTF-QoL. Patients that were ≥ 40 years scored significantly worse on the physical functioning scale of the EORTC QLQ-C30, while younger patients (18–39 years) scored significantly worse on several DTF-QoL subscales. Differences in the DTF-QoL subscales were found for tumour location, time since diagnosis and the presence of recurrent disease. Furthermore, treatments other than AS or surgery only, female sex, younger age and the presence of comorbidities were most frequently associated with worse scores on the DTF-QoL subscales. This study showed that (DTF-specific) HRQoL differs between groups of DTF patients. Awareness of these HRQoL differences could help to provide better, personalised care that is tailored to the needs of a specific subgroup.
Unraveling the Biology of Epithelioid Hemangioendothelioma, a TAZ–CAMTA1 Fusion Driven Sarcoma
Authors: Seavey Caleb , Pobbati Ajaybabu , Rubin Brian
Published: June 2022

The activities of YAP and TAZ, the end effectors of the Hippo pathway, are consistently altered in cancer, and this dysregulation drives aggressive tumor phenotypes. While the actions of these two proteins aid in tumorigenesis in the majority of cancers, the dysregulation of these proteins is rarely sufficient for initial tumor development. Herein, we present a unique TAZ-driven cancer, epithelioid hemangioendothelioma (EHE), which harbors a WWTR1(TAZ)–CAMTA1 gene fusion in at least 90% of cases. Recent investigations have elucidated the mechanisms by which YAP/TAP-fusion oncoproteins function and drive tumorigenesis. This review presents a critical evaluation of this recent work, with a particular focus on how the oncoproteins alter the normal activity of TAZ and YAP, and, concurrently, we generate a framework for how we can target the gene fusions in patients. Since EHE represents a paradigm of YAP/TAZ dysregulation in cancer, targeted therapies for EHE may also be effective against other YAP/TAZ-dependent cancers.
Differential HIF2α Protein Expression in Human Carotid Body and Adrenal Medulla under Physiologic and Tumorigenic Conditions
Authors: Celada Lucía , Cubiella Tamara , San-Juan-Guardado Jaime , San José Martínez Andrés , Valdés Nuria , Jiménez-Fonseca Paula , Díaz Ignacio , Enguita Jose María , Astudillo Aurora , Álvarez-González Enol , Sierra Luisa María , Chiara María-Dolores
Published: June 2022

Hypoxia-inducible factors (HIF) 2α and 1α are the major oxygen-sensing molecules in eukaryotic cells. HIF2α has been pathogenically linked to paraganglioma and pheochromocytoma (PPGL) arising in sympathetic paraganglia or the adrenal medulla (AM), respectively. However, its involvement in the pathogenesis of paraganglioma arising in the carotid body (CB) or other parasympathetic ganglia in the head and neck (HNPGL) remains to be defined. Here, we retrospectively analyzed HIF2α by immunohistochemistry in 62 PPGL/HNPGL and human CB and AM, and comprehensively evaluated the HIF-related transcriptome of 202 published PPGL/HNPGL. We report that HIF2α is barely detected in the AM, but accumulates at high levels in PPGL, mostly (but not exclusively) in those with loss-of-function mutations in VHL and genes encoding components of the succinate dehydrogenase (SDH) complex. This is associated with upregulation of EPAS1 and the HIF2α-regulated genes COX4I2 and ADORA2A. In contrast, HIF2α and HIF2α-regulated genes are highly expressed in CB and HNPGL, irrespective of VHL and SDH dysfunctions. We also found that HIF2α and HIF1α protein expressions are not correlated in PPGL nor HNPGL. In addition, HIF1α-target genes are almost exclusively overexpressed in VHL-mutated HNPGL/PPGL. Collectively, the data suggest that involvement of HIF2α in the physiology and tumor pathology of human paraganglia is organ-of-origin-dependent and HIF1α-independent.
Context-Dependent Effects Explain Divergent Prognostic Roles of Tregs in Cancer
Authors: Amblard Elise , Soumelis Vassili
Published: June 2022

Assessing cancer prognosis is a challenging task, given the heterogeneity of the disease. Multiple features (clinical, environmental, genetic) have been used for such assessments. The tumor immune microenvironment (TIME) is a key feature, and describing the impact of its many components on cancer prognosis is an active field of research. The complexity of the tumor microenvironment context makes it difficult to use the TIME to assess prognosis, as demonstrated by the example of regulatory T cells (Tregs). The effect of Tregs on prognosis is ambiguous, with different studies considering them to be negative, positive or neutral. We focused on five different cancer types (breast, colorectal, gastric, lung and ovarian). We clarified the definition of Tregs and their utility for assessing cancer prognosis by taking the context into account via the following parameters: the Treg subset, the anatomical location of these cells, and the neighboring cells. With a meta-analysis on these three parameters, we were able to clarify the prognostic role of Tregs. We found that CD45RO+ Tregs had a reproducible negative effect on prognosis across cancer types, and we gained insight into the contributions of the anatomical location of Tregs and of their neighboring cells on their prognostic value. Our results suggest that Tregs play a similar prognostic role in all cancer types. We also establish guidelines for improving the design of future studies addressing the pathophysiological role of Tregs in cancer.
Hg0 Removal by a Palygorskite and Fly Ash Supported MnO2-CeO2 Catalyst at Low Temperature
Authors: Wang Junwei , Jiang Caihong , Shi Liming , Xue Zhifeng , Wang Xie , Xu Can , Zhang Xianlong , Zhang Jianli
Published: June 2022

MnO2-CeO2/PG-FA catalysts were prepared by supporting MnO2-CeO2 to PG-FA and used to remove Hg0 in simulated flue gas. The results show that MnO2-CeO2/PG-FA catalyst had excellent and stable Hg0 removal activity, which was mainly due to the combination effect of the catalytic oxidation activity by MnO2-CeO2 and the adsorption ability by PG-FA. Mn8-Ce0.5/PG-FA (with 8.0% MnO2 and 0.5% CeO2 loading) catalyst showed the highest Hg0 removal efficiency at 140 °C and Hg0 removal efficiency could be maintained above 95% with the space velocity of 6000 h−1 and Hg0 concentration of 160 μg/m3. O2 promoted Hg0 removal by MnO2-CeO2/PG-FA catalyst, while SO2 and H2O had inhibitory effects. In the presence of O2, the inhibitory effect of SO2 and H2O can be obviously weakened. MnO2-CeO2/PG-FA catalysts were characterized with scanning electron microscope (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and temperature-programmed desorption experiments (TPD). The results of SEM and XRD showed that the active components MnO2-CeO2 dispersed well on the surface of PG-FA support. The results of XPS and TPD show that the Hg0 removal process over MnO2-CeO2/PG-FA catalyst included adsorption and oxidation, HgO and HgSO4 were generated and adsorbed on the catalyst. MnO2-CeO2/PG-FA catalyst also showed excellent regeneration performance after Hg0 removal.
CFTR Rescue by Lumacaftor (VX-809) Induces an Extensive Reorganization of Mitochondria in the Cystic Fibrosis Bronchial Epithelium
Authors: Braccia Clarissa , Christopher Josie A. , Crook Oliver M. , Breckels Lisa M. , Queiroz Rayner M. L. , Liessi Nara , Tomati Valeria , Capurro Valeria , Bandiera Tiziano , Baldassari Simona , Pedemonte Nicoletta , Lilley Kathryn S. , Armirotti Andrea
Published: June 2022

Background: Cystic Fibrosis (CF) is a genetic disorder affecting around 1 in every 3000 newborns. In the most common mutation, F508del, the defective anion channel, CFTR, is prevented from reaching the plasma membrane (PM) by the quality check control of the cell. Little is known about how CFTR pharmacological rescue impacts the cell proteome. Methods: We used high-resolution mass spectrometry, differential ultracentrifugation, machine learning and bioinformatics to investigate both changes in the expression and localization of the human bronchial epithelium CF model (F508del-CFTR CFBE41o-) proteome following treatment with VX-809 (Lumacaftor), a drug able to improve the trafficking of CFTR. Results: The data suggested no stark changes in protein expression, yet subtle localization changes of proteins of the mitochondria and peroxisomes were detected. We then used high-content confocal microscopy to further investigate the morphological and compositional changes of peroxisomes and mitochondria under these conditions, as well as in patient-derived primary cells. We profiled several thousand proteins and we determined the subcellular localization data for around 5000 of them using the LOPIT-DC spatial proteomics protocol. Conclusions: We observed that treatment with VX-809 induces extensive structural and functional remodelling of mitochondria and peroxisomes that resemble the phenotype of healthy cells. Our data suggest additional rescue mechanisms of VX-809 beyond the correction of aberrant folding of F508del-CFTR and subsequent trafficking to the PM.
Perturbation of Cortical Excitability in a Conditional Model of PCDH19 Disorder
Authors: Lamers Didi , Landi Silvia , Mezzena Roberta , Baroncelli Laura , Pillai Vinoshene , Cruciani Federica , Migliarini Sara , Mazzoleni Sara , Pasqualetti Massimo , Passafaro Maria , Bassani Silvia , Ratto Gian Michele
Published: June 2022

PCDH19 epilepsy (DEE9) is an X-linked syndrome associated with cognitive and behavioral disturbances. Since heterozygous females are affected, while mutant males are spared, it is likely that DEE9 pathogenesis is related to disturbed cell-to-cell communication associated with mosaicism. However, the effects of mosaic PCDH19 expression on cortical networks are unknown. We mimicked the pathology of DEE9 by introducing a patch of mosaic protein expression in one hemisphere of the cortex of conditional PCDH19 knockout mice one day after birth. In the contralateral area, PCDH19 expression was unaffected, thus providing an internal control. In this model, we characterized the physiology of the disrupted network using local field recordings and two photon Ca2+ imaging in urethane anesthetized mice. We found transient episodes of hyperexcitability in the form of brief hypersynchronous spikes or bursts of field potential oscillations in the 9–25 Hz range. Furthermore, we observed a strong disruption of slow wave activity, a crucial component of NREM sleep. This phenotype was present also when PCDH19 loss occurred in adult mice, demonstrating that PCDH19 exerts a function on cortical circuitry outside of early development. Our results indicate that a focal mosaic mutation of PCDH19 disrupts cortical networks and broaden our understanding of DEE9.
The Association of MEG3 lncRNA with Nuclear Speckles in Living Cells
Authors: Hasenson Sarah E. , Alkalay Ella , Atrash Mohammad K. , Boocholez Alon , Gershbaum Julianna , Hochberg-Laufer Hodaya , Shav-Tal Yaron
Published: June 2022

Nuclear speckles are nuclear bodies containing RNA-binding proteins as well as RNAs including long non-coding RNAs (lncRNAs). Maternally expressed gene 3 (MEG3) is a nuclear retained lncRNA found to associate with nuclear speckles. To understand the association dynamics of MEG3 lncRNA with nuclear speckles in living cells, we generated a fluorescently tagged MEG3 transcript that could be detected in real time. Under regular conditions, transient association of MEG3 with nuclear speckles was observed, including a nucleoplasmic fraction. Transcription or splicing inactivation conditions, known to affect nuclear speckle structure, showed prominent and increased association of MEG3 lncRNA with the nuclear speckles, specifically forming a ring-like structure around the nuclear speckles. This contrasted with metastasis-associated lung adenocarcinoma (MALAT1) lncRNA that is normally highly associated with nuclear speckles, which was released and dispersed in the nucleoplasm. Under normal conditions, MEG3 dynamically associated with the periphery of the nuclear speckles, but under transcription or splicing inhibition, MEG3 could also enter the center of the nuclear speckle. Altogether, using live-cell imaging approaches, we find that MEG3 lncRNA is a transient resident of nuclear speckles and that its association with this nuclear body is modulated by the levels of transcription and splicing activities in the cell.
Aberrant Synaptic Pruning in CNS Diseases: A Critical Player in HIV-Associated Neurological Dysfunction?
Authors: Watson Zachary , Tang Shao-Jun
Published: June 2022

Even in the era of effective antiretroviral therapies, people living with Human Immunodeficiency Virus (HIV) are burdened with debilitating neurological dysfunction, such as HIV-associated neurocognitive disorders (HAND) and HIV-associated pain, for which there are no FDA approved treatments. Disruption to the neural circuits of cognition and pain in the form of synaptic degeneration is implicated in developing these dysfunctions. Glia-mediated synaptic pruning is a mechanism of structural plasticity in the healthy central nervous system (CNS), but recently, it has been discovered that dysregulated glia-mediated synaptic pruning is the cause of synaptic degeneration, leading to maladaptive plasticity and cognitive deficits in multiple diseases of the CNS. Considering the essential contribution of activated glial cells during the development of HAND and HIV-associated pain, it is possible that glia-mediated synaptic pruning is the causative mechanism of synaptic degeneration induced by HIV. This review will analyze the known examples of synaptic pruning during disease in order to better understand how this mechanism could contribute to the progression of HAND and HIV-associated pain.
The Tumor-Specific Expression of L1 Retrotransposons Independently Correlates with Time to Relapse in Hormone-Negative Breast Cancer Patients
Authors: Berrino Enrico , Miglio Umberto , Bellomo Sara Erika , Debernardi Carla , Bragoni Alberto , Petrelli Annalisa , Cascardi Eliano , Giordano Silvia , Montemurro Filippo , Marchiò Caterina , Venesio Tiziana , Sapino Anna
Published: June 2022

Background: Long-Interspersed Nuclear Element (L1) retrotransposons are silenced in healthy tissues but unrepressed in cancer. Even if L1 reactivation has been associated with reduced overall survival in breast cancer (BC) patients, a comprehensive correlation with clinicopathological features is still missing. Methods: Using quantitative, reverse-transcription PCR, we assessed L1 mRNA expression in 12 BC cells, 210 BC patients and in 47 normal mammary tissues. L1 expression was then correlated with molecular and clinicopathological data. Results: We identified a tumor-exclusive expression of L1s, absent in normal mammary cells and tissues. A positive correlation between L1 expression and tumor dedifferentiation, lymph-node involvement and increased immune infiltration was detected. Molecular subtyping highlighted an enrichment of L1s in basal-like cells and cancers. By exploring disease-free survival, we identified L1 overexpression as an independent biomarker for patients with a high risk of recurrence in hormone-receptor-negative BCs. Conclusions: Overall, L1 reactivation identified BCs with aggressive features and patients with a worse clinical fate.
Diving into the Evolutionary History of HSC70-Linked Selective Autophagy Pathways: Endosomal Microautophagy and Chaperone-Mediated Autophagy
Authors: Schnebert Simon , Goguet Maxime , Vélez Emilio J. , Depincé Alexandra , Beaumatin Florian , Herpin Amaury , Seiliez Iban
Published: June 2022

Autophagy is a pleiotropic and evolutionarily conserved process in eukaryotes that encompasses different types of mechanisms by which cells deliver cytoplasmic constituents to the lysosome for degradation. Interestingly, in mammals, two different and specialized autophagic pathways, (i) the chaperone-mediated autophagy (CMA) and (ii) the endosomal microautophagy (eMI), both rely on the use of the same cytosolic chaperone HSPA8 (also known as HSC70) for targeting specific substrates to the lysosome. However, this is not true for all organisms, and differences exist between species with respect to the coexistence of these two autophagic routes. In this paper, we present an in-depth analysis of the evolutionary history of the main components of CMA and eMI and discuss how the observed discrepancies between species may contribute to improving our knowledge of these two functions and their interplays.
Exosome-Mediated Immunosuppression in Tumor Microenvironments
Authors: Xie Qi-Hui , Zheng Ji-Qi , Ding Jia-Yi , Wu Yu-Fei , Liu Luisa , Yu Zi-Li , Chen Gang
Published: June 2022

Exosomes are membranous structures secreted by nearly all cell types. As critical messengers for intercellular communication, exosomes deliver bioactive cargoes to recipient cells and are involved in multiple physiopathological processes, including immunoregulation. Our pioneering study revealed that cancer cells release programmed death-ligand 1-positive exosomes into the circulation to counter antitumor immunity systemically via T cells. Tumor cell-derived exosomes (TDEs) also play an immunosuppressive role in other immunocytes, including dendritic cells (DCs), macrophages, natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). Moreover, exosomes secreted by nontumor cells in the tumor microenvironments (TMEs) also exert immunosuppressive effects. This review systematically provides a summary of the immunosuppression induced by exosomes in tumor microenvironments, which modulates tumor growth, invasion, metastasis, and immunotherapeutic resistance. Additionally, therapeutic strategies targeting the molecular mechanism of exosome-mediated tumor development, which may help overcome several obstacles, such as immune tolerance in oncotherapy, are also discussed. Detailed knowledge of the specific functions of exosomes in antitumor immunity may contribute to the development of innovative treatments.
The Long Non-Coding RNA GOMAFU in Schizophrenia: Function, Disease Risk, and Beyond
Authors: Zakutansky Paul M. , Feng Yue
Published: June 2022

Neuropsychiatric diseases are among the most common brain developmental disorders, represented by schizophrenia (SZ). The complex multifactorial etiology of SZ remains poorly understood, which reflects genetic vulnerabilities and environmental risks that affect numerous genes and biological pathways. Besides the dysregulation of protein-coding genes, recent discoveries demonstrate that abnormalities associated with non-coding RNAs, including microRNAs and long non-coding RNAs (lncRNAs), also contribute to the pathogenesis of SZ. lncRNAs are an actively evolving family of non-coding RNAs that harbor greater than 200 nucleotides but do not encode for proteins. In general, lncRNA genes are poorly conserved. The large number of lncRNAs specifically expressed in the human brain, together with the genetic alterations and dysregulation of lncRNA genes in the SZ brain, suggests a critical role in normal cognitive function and the pathogenesis of neuropsychiatric diseases. A particular lncRNA of interest is GOMAFU, also known as MIAT and RNCR2. Growing evidence suggests the function of GOMAFU in governing neuronal development and its potential roles as a risk factor and biomarker for SZ, which will be reviewed in this article. Moreover, we discuss the potential mechanisms through which GOMAFU regulates molecular pathways, including its subcellular localization and interaction with RNA-binding proteins, and how interruption to GOMAFU pathways may contribute to the pathogenesis of SZ.
The Effects of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Erythropoietin, and Their Interactions in Angiogenesis: Implications in Retinopathy of Prematurity
Authors: Cung Thaonhi , Wang Haibo , Hartnett M. Elizabeth
Published: June 2022

Retinopathy of prematurity (ROP) is a leading cause of vision impairment and blindness in premature infants. Oxidative stress is implicated in its pathophysiology. NADPH oxidase (NOX), a major enzyme responsible for reactive oxygen species (ROS) generation in endothelial cells, has been studied for its involvement in physiologic and pathologic angiogenesis. Erythropoietin (EPO) has gained interest recently due to its tissue protective and angiogenic effects, and it has been shown to act as an antioxidant. In this review, we summarize studies performed over the last five years regarding the role of various NOXs in physiologic and pathologic angiogenesis. We also discuss the effect of EPO in tissue and vasoprotection, and the intersection of EPO and NOX-mediated oxidative stress in angiogenesis and the pathophysiology of ROP.
Generating iPSCs with a High-Efficient, Non-Invasive Method—An Improved Way to Cultivate Keratinocytes from Plucked Hair for Reprogramming
Authors: Wüstner Lisa S. , Klingenstein Moritz , Frey Karl G. , Nikbin Mohammad R. , Milazzo Alfio , Kleger Alexander , Liebau Stefan , Klingenstein Stefanie
Published: June 2022

Various somatic cell types are suitable for induced pluripotency reprogramming, such as dermal fibroblasts, mesenchymal stem cells or hair keratinocytes. Harvesting primary epithelial keratinocytes from plucked human hair follicles (HFs) represents an easy and non-invasive alternative to a fibroblast culture from invasive skin biopsies. Nevertheless, to facilitate and simplify the process, which can be divided into three main steps (collecting, culturing and reprogramming), the whole procedure of generating hair keratinocytes has to be revised and upgraded continuously. In this study, we address advancements and approaches which improve the generation and handling of primary HF-derived keratinocytes tremendously, e.g., for iPSCs reprogramming. We not only evaluated different serum- and animal-origin-free media, but also supplements and coating solutions for an enhanced protocol. Here, we demonstrate the importance of speed and accuracy in the collecting step, as well as the choice of the right transportation medium. Our results lead to a more defined approach that further increases the reliability of downstream experiments and inter-laboratory reproducibility. These improvements will make it possible to obtain keratinocytes from plucked human hair for the generation of donor-specific iPSCs easier and more efficient than ever before, whilst preserving a non-invasive capability.
Platelets at the Crossroads of Pro-Inflammatory and Resolution Pathways during Inflammation
Authors: Ludwig Nadine , Hilger Annika , Zarbock Alexander , Rossaint Jan
Published: June 2022

Platelets are among the most abundant cells in the mammalian circulation. Classical platelet functions in hemostasis and wound healing have been intensively explored and are generally accepted. During the past decades, the research focus broadened towards their participation in immune-modulatory events, including pro-inflammatory and, more recently, inflammatory resolution processes. Platelets are equipped with a variety of abilities enabling active participation in immunological processes. Toll-like receptors mediate the recognition of pathogens, while the release of granule contents and microvesicles promotes direct pathogen defense and an interaction with leukocytes. Platelets communicate and physically interact with neutrophils, monocytes and a subset of lymphocytes via soluble mediators and surface adhesion receptors. This interaction promotes leukocyte recruitment, migration and extravasation, as well as the initiation of effector functions, such as the release of extracellular traps by neutrophils. Platelet-derived prostaglandin E2, C-type lectin-like receptor 2 and transforming growth factor β modulate inflammatory resolution processes by promoting the synthesis of pro-resolving mediators while reducing pro-inflammatory ones. Furthermore, platelets promote the differentiation of CD4+ T cells in T helper and regulatory T cells, which affects macrophage polarization. These abilities make platelets key players in inflammatory diseases such as pneumonia and the acute respiratory distress syndrome, including the pandemic coronavirus disease 2019. This review focuses on recent findings in platelet-mediated immunity during acute inflammation.
Adolescent and Juvenile Idiopathic Scoliosis: Which Patients Obtain Good Results with 12 Hours of Cheneau–Toulouse–Munster Nighttime Bracing?
Authors: De Chelle Gautier , Rampal Virginie , Bentellis Imad , Fernandez Arnaud , Bertoncelli Carlo , Clément Jean-Luc , Solla Federico
Published: June 2022

Background: The results of 12 h nighttime Cheneau–Toulouse–Munster (CTM) brace wear on adolescent idiopathic scoliosis are poorly described. Objective: The main objective was to analyze the efficiency of 12 h nighttime CTM brace wear on adolescent idiopathic scoliosis. The secondary objective was to identify the factors influencing good results. Methods: One hundred and fifty consecutive patients treated between 2006 and 2017 were retrospectively analyzed with subgroup analysis for the main curve pattern (main thoracic or main lumbar). The inclusion criteria were evolutive scoliosis, 12 h nighttime CTM brace wear, Risser stages 0-1-2 at the time of the prescription, and Cobb angle below 45 degrees. Success was defined as no surgery, and the main curve Cobb angle (CA) progression ≤5°. The overcurve was defined as the proximal thoracic curve above the main thoracic and mid-thoracic above the main lumbar curves. A logistic regression model was built to assess the predictors of success. RESULTS: Overall success was 70%: 60% for main thoracic (MT) and 84% for main lumbar scoliosis (ML) (p = 0.003). Efficacy was 62% at Risser stage 0 and 78% at Risser stage 1–2 (p = 0.054). For MT, failure was associated with high in-brace sagittal C7 tilt (Odds Ratio = 0.72, p = 0.014) and low initial overcurve CA (Odds Ratio = 0.42, p = 0.044). For ML, a high standing height was associated with success (OR = 1.42, p = 0.035), and frontal unbalanced C7 tilt was associated with failure (OR = 0.43, p = 0.02). Conclusion: Twelve-hour nighttime CTM brace wear provided good results for main lumbar curves with balanced frontal C7 tilt. For MT, this treatment is indicated if the in-brace sagittal C7 tilt is well balanced from Risser stage 2.