bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple-Criteria Fuzzy Optimization of the Heat Treatment Processes for Two Steel Rolled Products
Authors: Dymova Ludmila , Kaczmarek Krzysztof , Sevastjanov Pavel
Published: March 2021

This paper presents a developed method for fuzzy multiple-criteria optimization of the rolled-steel heat treatment processes in the modern metallurgical plant. At the first stage of the study, by means of passive industrial experiments or a mathematical simulation of heat transfer processes, and using statistical methods, the regression dependencies of the output parameters of process quality on the input variables that are technological parameters are established. Then, based on the quality parameters, membership functions are formed that represent local criteria of the process quality, and their ranks are calculated using the matrix of pairwise comparisons. The practically useful methodology of the fuzzy multiple-criteria optimization of technological processes is proposed. To illustrate this methodology’s practical efficiency, the solutions of two optimization problems are found by maximizing the global criterion that aggregates local criteria using their ranks. It is shown that the efficiency of the obtained optimal heat treatment modes significantly exceeds the efficiency of the technology used earlier in the plant.
Impact of Climate Change on Past Indian Monsoon and Circulation: A Perspective Based on Radiogenic and Trace Metal Geochemistry
Authors: Rashid Harunur , Wang Yang , Gourlan Alexandra T.
Published: March 2021

The Indian summer monsoon (ISM), one of the dramatic illustrations of seasonal hydrological variability in the climate system, affects billions of lives. The ISM dominantly controls the northern Indian Ocean sea-surface salinity, mostly in the Bay of Bengal and the Andaman Sea, by the Ganga-Brahmaputra-Meghna and Irrawaddy-Salween rivers outflow and direct rainfall. In the past decade, numerous studies have used radiogenic neodymium (εNd) isotopes of seawater to link Indian subcontinent erosion and the ensuing increase in discharge that results in changes in the north Indian Ocean sea surface. Here we synthesized the state of the ISM and ocean circulation using the neodymium and hafnium isotopes from north Indian Ocean deep-sea sediments. Our data suggest that the Bay of Bengal and north Indian Ocean sea-surface conditions were most likely modulated by changes in the ISM strength during the last glacial-interglacial cycle. These findings contrast to the hypothesis that suggests that the bottom water neodymium isotopes of the northern Indian Ocean were modulated by switching between two distant sources, namely North Atlantic Deep Water and Antarctic bottom water. Furthermore, the consistency between the neodymium and hafnium isotopes during the last glacial maximum and Holocene suggests a weak and dry ISM and strong and wet conditions, respectively. These data also indicate that the primary source of these isotopes was the Himalayas. Our results support the previously published paleo-proxy records, indicating weak and strong monsoons for the same periods. Moreover, our data further support the hypothesis that the northern Indian Ocean neodymium isotopes were decoupled from the global ocean neodymium budget due to the greater regional influence by the great Ganga-Brahmaputra-Meghna and Irrawaddy-Salween discharge draining the Indian subcontinent to the Bay of Bengal and the Andaman Sea.
Morphology, Mineralogy, and Chemistry of Atmospheric Aerosols Nearby an Active Mining Area: Aljustrel Mine (SW Portugal)
Authors: Barroso Ana , Mogo Sandra , Silva M. Manuela V. G. , Cachorro Victoria , de Frutos Ángel
Published: March 2021

Mining activities increase contaminant levels in the environment, so it is crucial to study the particulate matter in these areas to understand the impacts on nearby urban areas and populations. This work was conducted close to the active mine of Aljustrel (Portugal), where black dust deposition is evident. PM10 samples were collected in two periods: 10–17 July and 1–10 November of 2018. Two different techniques were used: SEM-EDX for the individual characterization of the aerosols and ICP-MS to quantify the elemental concentration of 11 elements (Ca, Na, Fe, Mn, As, Cd, Cu, Sb, Pb, and Zn). In this region, the observed PM10 mass concentration was 20 to 47 µg m −3 (July) and 4 to 23 µg m−3 (November), which is lower than the limit of 50 μg m−3 established in the European Directive. The individual characterization of 2006 particles by SEM-EDX shows oxides (17%) and sulfides (10%), while Na, Si, Fe, S, Al, and Cu are the elements with the most representativeness in all the analyzed particles. The ICP-MS results indicate that the daily elemental concentration in the samples collected in July is higher than November, and only As exceeds the limit established for European legislation.
Temporal Distribution and Gas/Particle Partitioning of Polycyclic Aromatic Hydrocarbons (PAHs) in the Atmosphere of Strasbourg, France
Authors: Chimjarn Supansa , Delhomme Olivier , Millet Maurice
Published: March 2021

Gas and particulate phase ambient air concentrations of polycyclic aromatic hydrocarbons (Ʃ16PAHs) were determined in Strasbourg, a large city located in the Alsace region of northeastern France, from May 2018 to March 2020, to study the evolution of their temporal variations and their potential origins. The analysis of PAHs was performed using a global analytical method permitting the quantification of pesticides, PAHs, and polychlorobiphenyls (PCBs). Filters and Carbon doped silicon carbide NMC@SiC foams were extracted by accelerated solvent extraction (ASE) followed by a solid-phase extraction (SPE). Afterwards, extracts were analyzed using gas chromatography coupled to tandem mass spectrometry (GC-MS/MS). Prior to analysis, a pre-concentration step based on solid-phase microextraction (SPME) was used with a polydimethylsiloxane (PDMS) 100 µm fiber. The average total (gas plus particulate) concentration of Ʃ16PAHs varied from 0.51 to 117.31 ng m−3 with a mean of 16.87 ng m−3, with higher concentrations in the cold season of more than 2.5-fold and 6-fold that in the warm season for the gas and particulate phases, respectively. Moreover, low molecular weight (LMW) (2-ring and 3-ring) and medium molecular weight (MMW) (4-ring) PAHs contribute dominantly to the gas phase, while the particulate phase is associated with MMW (4-ring) and high molecular weight (HMW) (5-ring and 6-ring) PAHs. Gas/particle partitioning coefficient (log Kp) was calculated, and values varied between −4.13 and −1.49. It can be seen that the log Kp increased with the molecular weight of the PAHs and that the log Kp is different between cold and warm seasons for HMW PAHs but not for LMW PAHs. Diagnostic ratios of PAHs, which were employed to estimate the primary source of PAHs in Strasbourg, indicate that fuel combustion and biomass/coal burning are the possible origins of PAHs in Strasbourg’s atmosphere.
Brewery Packaging in a Post-COVID Economy within the United States
Authors: Pitts Eric R. , Witrick Katherine
Published: March 2021

The 2020 pandemic caused by the novel coronavirus, SARS-CoV-2, also referred to as the COVID-19 [named for the disease caused by the virus] pandemic, shook the world to its core. Not only were populations hurt by the virus physically, the pandemic had deep repercussions economically as well. One of the industries severely impacted by the implications of the 2020 COVID-19 pandemic was the brewing industry, particularly that of the United States. The economic turmoil and uncertainty were felt by both macro and micro brewers alike. Draft beer sales virtually dried up overnight as state-imposed shutdowns closed bars, restaurants, and taprooms as a means to curb the spread of the virus. There were supply chain and logistical issues that arose during the pandemic due to not only closures within the brewing industry but supporting industries such as printers and shippers. In some cases, entire business models had to be turned completely on their head in an instant and business pivots had to be made. The year 2020 was wrought with challenges faced by the brewing industry. There was one saving grace however that kept many breweries afloat during the pandemic, and that was packaged beverage sales, especially those packages intended for off-site consumption. Set forth by trends of the pre-pandemic years aluminum cans and canning reigned supreme for the craft brewing market and allowed breweries to get product into the hands of consumers and ultimately allowed some breweries to stay open. Other options breweries had included the use of glass growlers or aluminum crowlers as a means to sell draft products to-go. The resourcefulness of many brewery owners was tested in 2020 and many rose to the challenge. This report aims to examine several of the challenges, pivots, and solutions packaging provided to the beer industry during the pandemic.
Targeted Dorsal Dentate Gyrus or Whole Brain Irradiation in Juvenile Mice Differently Affects Spatial Memory and Adult Hippocampal Neurogenesis
Authors: Serrano Céline , Dos Santos Morgane , Kereselidze Dimitri , Beugnies Louison , Lestaevel Philippe , Poirier Roseline , Durand Christelle
Published: March 2021

The cognitive consequences of postnatal brain exposure to ionizing radiation (IR) at low to moderate doses in the adult are not fully established. Because of the advent of pediatric computed tomography scans used for head exploration, improving our knowledge of these effects represents a major scientific challenge. To evaluate how IR may affect the developing brain, models of either whole brain (WB) or targeted dorsal dentate gyrus (DDG) irradiation in C57Bl/6J ten-day-old male mice were previously developed. Here, using these models, we assessed and compared the effect of IR (doses range: 0.25–2 Gy) on long-term spatial memory in adulthood using a spatial water maze task. We then evaluated the effects of IR exposure on adult hippocampal neurogenesis, a form of plasticity involved in spatial memory. Three months after WB exposure, none of the doses resulted in spatial memory impairment. In contrast, a deficit in memory retrieval was identified after DDG exposure for the dose of 1 Gy only, highlighting a non-monotonic dose-effect relationship in this model. At this dose, a brain irradiated volume effect was also observed when studying adult hippocampal neurogenesis in the two models. In particular, only DDG exposure caused alteration in cell differentiation. The most deleterious effect observed in adult hippocampal neurogenesis after targeted DDG exposure at 1 Gy may contribute to the memory retrieval deficit in this model. Altogether these results highlight the complexity of IR mechanisms in the brain that can lead or not to cognitive disorders and provide new knowledge of interest for the radiation protection of children.
Leptospira fainei Detected in Testicles and Epididymis of Wild Boar (Sus scrofa)
Authors: Cilia Giovanni , Bertelloni Fabrizio , Cerri Domenico , Fratini Filippo
Published: March 2021

Leptospirosis is a re-emerging and worldwide diffused zoonosis. Recently, the high importance of their epidemiology was explained by the intermediate Leptospira strains. Among these strains, Leptospira fainei was the first intermediate strain detected in domestic and wild swine. Wild boars (Sus scrofa) are well known as a reservoir, as well as all swine, for pathogenic Leptospira, but very little information is available concerning intermediate Leptospira infection. The investigation aim was to evaluate if intermediate Leptospira can infect the reproductive systems of wild boars hunted in the Tuscany region (Italy), as previously demonstrated for pathogenic ones. The reproductive system tissue (testicles, epididymides, uteri), and placentas and fetuses, were collected from 200 regularly hunted animals. Bacteriological examination and real-time PCR were performed to detect intermediate Leptospira DNA. Unfortunately, no isolates were obtained. Using real-time PCR, in six (3%) male organs (both testicles and epididymis), intermediate Leptospira DNA was found. The amplification of the 16S rRNA gene identified that all DNA obtained belong to Leptospira fainei. The results of this investigation highlighted for the first time the localization of Leptospira fainei in the male wild boar reproductive system, opening up a new avenue to further investigate.
Extinction Risk Assessment of the Greek Endemic Flora
Authors: Kougioumoutzis Konstantinos , Kokkoris Ioannis P. , Panitsa Maria , Strid Arne , Dimopoulos Panayotis
Published: March 2021

Human-induced biodiversity decline has been on the rise for the past 250 years, due to various causes. What is equally troubling, is that we are unaware which plants are threatened and where they occur. Thus, we are far from reaching Aichi Biodiversity Target 2, i.e., assessing the extinction risk of most species. To that end, based on an extensive occurrence dataset, we performed an extinction risk assessment according to the IUCN Criteria A and B for all the endemic plant taxa occurring in Greece, one of the most biodiverse countries in Europe, in a phylogenetically-informed framework and identified the areas needing conservation prioritization. Several of the Greek endemics are threatened with extinction and fourteen endemics need to be prioritized, as they are evolutionary distinct and globally endangered. Mt. Gramos is identified as the most important conservation hotspot in Greece. However, a significant portion of the identified conservation hotspots is not included in any designated Greek protected area, meaning that the Greek protected areas network might need to be at least partially redesigned. In the Anthropocene era, where climate and land-use change are projected to alter biodiversity patterns and may force many species to extinction, our assessment provides the baseline for future conservation research, ecosystem services maintenance, and might prove crucial for the timely, systematic and effective aversion of plant extinctions in Greece.
Acid Dentin Lysate Failed to Modulate Bone Formation in Rat Calvaria Defects
Authors: Nasirzade Jila , Alccayhuaman Karol Alí Apaza , Kargarpour Zahra , Kuchler Ulrike , Strauss Franz Josef , Panahipour Layla , Kampleitner Carina , Heimel Patrick , Schwarz Frank , Gruber Reinhard
Published: March 2021

Autogenous tooth roots are increasingly applied as a grafting material in alveolar bone augmentation. Since tooth roots undergo creeping substitution similar to bone grafts, it can be hypothesized that osteoclasts release the growth factors stored in the dentin thereby influencing bone formation. To test this hypothesis, collagen membranes were either soaked in acid dentin lysates (ADL) from extracted porcine teeth or serum–free medium followed by lyophilization. Thereafter, these membranes covered standardized 5-mm-diameter critical-size defects in calvarial bone on rats. After four weeks of healing, micro-computed tomography and histological analyses using undecalcified thin ground sections were performed. Micro-computed tomography of the inner 4.5 mm calvaria defects revealed a median bone defect coverage of 91% (CI: 87–95) in the ADL group and 94% (CI: 65–100) in the control group, without significant differences between the groups (intergroup p > 0.05). Furthermore, bone volume (BV) was similar between ADL group (5.7 mm3, CI: 3.4–7.1) and control group (5.7 mm3, CI: 2.9–9.7). Histomorphometry of the defect area confirmed these findings with bone area values amounting to 2.1 mm2 (CI: 1.2–2.6) in the ADL group and 2.0 mm2 (CI: 1.1–3.0) in the control group. Together, these data suggest that acid dentin lysate lyophilized onto collagen membranes failed to modulate the robust bone formation when placed onto calvarial defects.
Drug–Microbiota Interaction in Colon Cancer Therapy: Impact of Antibiotics
Authors: Mohamed Ali , Menon Harry , Chulkina Marina , Yee Nelson S. , Pinchuk Irina V.
Published: March 2021

Colon adenocarcinoma is one of the most common malignancies, and it is highly lethal. Chemotherapy plays an important role in the treatment of colon cancer at various stages of the disease. The gut microbiome has emerged as a key player in colon cancer development and progression, and it can also alter the therapeutic agent’s efficacy and toxicities. Antibiotics can directly and/or indirectly affect the balance of the gut microbiome and, therefore, the clinical outcomes. In this article, we provided an overview of the composition of the gut microbiome under homeostasis and the mechanistic links between gut microbiota and colon cancer. The relationship between the use of oral antibiotics and colon cancer, as well as the impact of the gut microbiome on the efficacy and toxicities of chemotherapy in colon cancer, are discussed. Potential interventions to modulate microbiota and improve chemotherapy outcomes are discussed. Further studies are indicated to address these key gaps in the field and provide a scientific basis for the design of novel microbiota-based approaches for prevention/use as adjuvant therapeutics for patients with colon cancer.
Food Safety in Post-COVID-19 Pandemic: Challenges and Countermeasures
Authors: Zhang Weimin , He Huiyu , Zhu Lin , Liu Guozhen , Wu Long
Published: March 2021

Understanding food safety hazard risks is essential to avoid potential negative heath impacts in the food supply chain in a post-COVID-19 pandemic era. Development of strategies for virus direction in foods plays an important role in food safety and verification. Early warning, tracing, and detection should be implemented as an integrated system in order to mitigate thecoronavirus disease 2019 (COVID-19) outbreak, in which the detection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is critical as it not only concerns screening of populations but also monitoring of possible contaminated sources such as the food supply chain. In this review, we point out the consequences in different aspects of our daily life in the post-COVID-19 pandemic from the perspective of the food supply chain and the food industry. We summarize the possible transmission routes of COVID-19 in the food supply chain before exploring the development of corresponding detection tools of SARS-CoV-2. Accordingly, we compare different detection methods for the virus in foods, including different pretreatments of food matrices in the virus detection. Finally, the future perspectives are proposed.
A Risk Analysis‐Best Worst Method Based Model for Selection of the Most Appropriate Contract Strategy for Onshore Drilling Projects in the Iranian Petroleum Industry
Authors: Faraji Amir , Rashidi Maria , Khadir Pegah , Perera Srinath
Published: March 2021

The pre-project planning phase has a significant impact on the achievement of project objectives because during this stage, major decisions including involving contract strategies are made with a high degree of uncertainty. Studies show that the contract type can play a unique role in the achievement of project success. On the other hand, drilling projects can be considered as one of the most critical types of projects in the petroleum industry. In this research, a novel risk based best-worst method (risk-BWM) is proposed for solving the issue of selecting the best contract strategy. A three level methodology was designed; firstly, the risk breakdown structure (RBS) of drilling projects was created in four levels including one heading in level 0, eight main areas of risk in level 1, 34 sub-areas of risk in level 2, and finally, 217 risk items in level 3. Secondly and on the basis of BWM, the weights of risk factors were determined as the selection criteria and consequently the best and the worst criteria were specified. Finally, using pair-wise comparisons between six types of drilling prevalent in contracts, the most appropriate contract type was proposed. The contribution of this study is the development of a generic RBS for drilling projects and application of the risk factors for the first time for the selection of contract type using the BWM method, which has the potential of being adapted for other types of underground projects.
Cross-Linking Ligation and Sequencing of Hybrids (qCLASH) Reveals an Unpredicted miRNA Targetome in Melanoma Cells
Authors: Kozar Ines , Philippidou Demetra , Margue Christiane , Gay Lauren A. , Renne Rolf , Kreis Stephanie
Published: March 2021

MicroRNAs are key post-transcriptional gene regulators often displaying aberrant expression patterns in cancer. As microRNAs are promising disease-associated biomarkers and modulators of responsiveness to anti-cancer therapies, a solid understanding of their targetome is crucial. Despite enormous research efforts, the success rates of available tools to reliably predict microRNAs (miRNA)-target interactions remains limited. To investigate the disease-associated miRNA targetome, we have applied modified cross-linking ligation and sequencing of hybrids (qCLASH) to BRAF-mutant melanoma cells. The resulting RNA-RNA hybrid molecules provide a comprehensive and unbiased snapshot of direct miRNA-target interactions. The regulatory effects on selected miRNA target genes in predicted vs. non-predicted binding regions was validated by miRNA mimic experiments. Most miRNA–target interactions deviate from the central dogma of miRNA targeting up to 60% interactions occur via non-canonical seed pairing with a strong contribution of the 3′ miRNA sequence, and over 50% display a clear bias towards the coding sequence of mRNAs. miRNAs targeting the coding sequence can directly reduce gene expression (miR-34a/CD68), while the majority of non-canonical miRNA interactions appear to have roles beyond target gene suppression (miR-100/AXL). Additionally, non-mRNA targets of miRNAs (lncRNAs) whose interactions mainly occur via non-canonical binding were identified in melanoma. This first application of CLASH sequencing to cancer cells identified over 8 K distinct miRNA–target interactions in melanoma cells. Our data highlight the importance non-canonical interactions, revealing further layers of complexity of post-transcriptional gene regulation in melanoma, thus expanding the pool of miRNA–target interactions, which have so far been omitted in the cancer field.
Functional States in Tumor-Initiating Cell Differentiation in Human Colorectal Cancer
Authors: Zowada Martina K. , Tirier Stephan M. , Dieter Sebastian M. , Krieger Teresa G. , Oberlack Ava , Chua Robert Lorenz , Huerta Mario , Ten Foo Wei , Laaber Karin , Park Jeongbin , Jechow Katharina , Müller Torsten , Kalxdorf Mathias , Kriegsmann Mark , Kriegsmann Katharina , Herbst Friederike , Krijgsveld Jeroen , Schneider Martin , Eils Roland , Glimm Hanno , Conrad Christian , Ball Claudia R.
Published: March 2021

Intra-tumor heterogeneity of tumor-initiating cell (TIC) activity drives colorectal cancer (CRC) progression and therapy resistance. Here, we used single-cell RNA-sequencing of patient-derived CRC models to decipher distinct cell subpopulations based on their transcriptional profiles. Cell type-specific expression modules of stem-like, transit amplifying-like, and differentiated CRC cells resemble differentiation states of normal intestinal epithelial cells. Strikingly, identified subpopulations differ in proliferative activity and metabolic state. In summary, we here show at single-cell resolution that transcriptional heterogeneity identifies functional states during TIC differentiation. Furthermore, identified expression signatures are linked to patient prognosis. Targeting transcriptional states associated to cancer cell differentiation might unravel novel vulnerabilities in human CRC.
Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing
Authors: Kabakov Alexander E. , Yakimova Anna O.
Published: March 2021

Within aggressive malignancies, there usually are the “hypoxic zones”—poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. Both the lack of oxygen by itself and the hypoxia-responsive phenotypic modulations render tumor cells more radioresistant, so that hypoxic tumors are a serious challenge for radiotherapy. An understanding of causes of the radioresistance of hypoxic tumors would help to develop novel ways for overcoming this challenge. Molecular targets for and various approaches to radiosensitizing hypoxic tumors are considered in the present review. It is here analyzed how the hypoxia-induced cellular responses involving hypoxia-inducible factor-1, heat shock transcription factor 1, heat shock proteins, glucose-regulated proteins, epigenetic regulators, autophagy, energy metabolism reprogramming, epithelial–mesenchymal transition and exosome generation contribute to the radioresistance of hypoxic tumors or may be inhibited for attenuating this radioresistance. The pretreatments with a multitarget inhibition of the cancer cell adaptation to hypoxia seem to be a promising approach to sensitizing hypoxic carcinomas, gliomas, lymphomas, sarcomas to radiotherapy and, also, liver tumors to radioembolization.
Integrin αvβ3 Engagement Regulates Glucose Metabolism and Migration through Focal Adhesion Kinase (FAK) and Protein Arginine Methyltransferase 5 (PRMT5) in Glioblastoma Cells
Authors: Che Pulin , Yu Lei , Friedman Gregory K. , Wang Meimei , Ke Xiaoxue , Wang Huafeng , Zhang Wenbin , Nabors Burt , Ding Qiang , Han Xiaosi
Published: March 2021

Metabolic reprogramming promotes glioblastoma cell migration and invasion. Integrin αvβ3 is one of the major integrin family members in glioblastoma multiforme cell surface mediating interactions with extracellular matrix proteins that are important for glioblastoma progression. The role of αvβ3 integrin in regulating metabolic reprogramming and its mechanism of action have not been determined in glioblastoma cells. Integrin αvβ3 engagement with osteopontin promotes glucose uptake and aerobic glycolysis, while inhibiting mitochondrial oxidative phosphorylation. Blocking or downregulation of integrin αvβ3 inhibits glucose uptake and aerobic glycolysis and promotes mitochondrial oxidative phosphorylation, resulting in decreased migration and growth in glioblastoma cells. Pharmacological inhibition of focal adhesion kinase (FAK) or downregulation of protein arginine methyltransferase 5 (PRMT5) blocks metabolic shift toward glycolysis and inhibits glioblastoma cell migration and invasion. These results support that integrin αvβ3 and osteopontin engagement plays an important role in promoting the metabolic shift toward glycolysis and inhibiting mitochondria oxidative phosphorylation in glioblastoma cells. The metabolic shift in cell energy metabolism is coupled to changes in migration, invasion, and growth, which are mediated by downstream FAK and PRMT5 in glioblastoma cells.
MPscore: A Novel Predictive and Prognostic Scoring for Progressive Meningioma
Authors: Liu Feili , Qian Jin , Ma Chenkai
Published: March 2021

Meningioma is the most common tumor in central nervous system (CNS). Although most cases of meningioma are benign (WHO grade I) and curable by surgical resection, a few tumors remain diagnostically and therapeutically challenging due to the frequent recurrence and progression. The heterogeneity of meningioma revealed by DNA methylation profiling suggests the demand of subtyping for meningioma. Therefore, we performed a clustering analyses to characterize the progressive features of meningioma and constructed a meningioma progression score to predict the risk of the recurrence. A total of 179 meningioma transcriptome from RNA sequencing was included for progression subtype clustering. Four biologically distinct subtypes (subtype 1, subtype 2, subtype 3 and subtype 4) were identified. Copy number alternation and genomewide DNA methylation of each subtype was also characterized. Immune cell infiltration was examined by the microenvironment cell populations counter. All anaplastic meningiomas (7/7) and most atypical meningiomas (24/32) are enriched in subtype 3 while no WHO II or III meningioma presents in subtype 1, suggesting subtype 3 meningioma is a progressive subtype. Stemness index and immune response are also heterogeneous across four subtypes. Monocytic lineage is the most immune cell type in all meningiomas, except for subtype 1. CD8 positive T cells are predominantly observed in subtype 3. To extend the clinical utility of progressive meningioma subtyping, we constructed the meningioma progression score (MPscore) by the signature genes in subtype 3. The predictive accuracy and prognostic capacity of MPscore has also been validated in three independent cohort. Our study uncovers four biologically distinct subtypes in meningioma and the MPscore is potentially helpful in the recurrence risk prediction and response to treatments stratification in meningioma.
Advanced Pediatric Diffuse Pontine Glioma Murine Models Pave the Way towards Precision Medicine
Authors: Chen Zirong , Peng Peng , Zhang Xiaolin , Mania-Farnell Barbara , Xi Guifa , Wan Feng
Published: March 2021

Diffuse intrinsic pontine gliomas (DIPGs) account for ~15% of pediatric brain tumors, which invariably present with poor survival regardless of treatment mode. Several seminal studies have revealed that 80% of DIPGs harbor H3K27M mutation coded by HIST1H3B, HIST1H3C and H3F3A genes. The H3K27M mutation has broad effects on gene expression and is considered a tumor driver. Determination of the effects of H3K27M on posttranslational histone modifications and gene regulations in DIPG is critical for identifying effective therapeutic targets. Advanced animal models play critical roles in translating these cutting-edge findings into clinical trial development. Here, we review current molecular research progress associated with DIPG. We also summarize DIPG animal models, highlighting novel genomic engineered mouse models (GEMMs) and innovative humanized DIPG mouse models. These models will pave the way towards personalized precision medicine for the treatment of DIPGs.
Resistance to Molecularly Targeted Therapies in Melanoma
Authors: Patel Meet , Eckburg Adam , Gantiwala Shahina , Hart Zachary , Dein Joshua , Lam Katie , Puri Neelu
Published: March 2021

Malignant melanoma is the most aggressive type of skin cancer with invasive growth patterns. In 2021, 106,110 patients are projected to be diagnosed with melanoma, out of which 7180 are expected to die. Traditional methods like surgery, radiation therapy, and chemotherapy are not effective in the treatment of metastatic and advanced melanoma. Recent approaches to treat melanoma have focused on biomarkers that play significant roles in cell growth, proliferation, migration, and survival. Several FDA-approved molecular targeted therapies such as tyrosine kinase inhibitors (TKIs) have been developed against genetic biomarkers whose overexpression is implicated in tumorigenesis. The use of targeted therapies as an alternative or supplement to immunotherapy has revolutionized the management of metastatic melanoma. Although this treatment strategy is more efficacious and less toxic in comparison to traditional therapies, targeted therapies are less effective after prolonged treatment due to acquired resistance caused by mutations and activation of alternative mechanisms in melanoma tumors. Recent studies focus on understanding the mechanisms of acquired resistance to these current therapies. Further research is needed for the development of better approaches to improve prognosis in melanoma patients. In this article, various melanoma biomarkers including BRAF, MEK, RAS, c-KIT, VEGFR, c-MET and PI3K are described, and their potential mechanisms for drug resistance are discussed.
The Mechanical Fingerprint of Circulating Tumor Cells (CTCs) in Breast Cancer Patients
Authors: Nel Ivonne , Morawetz Erik W. , Tschodu Dimitrij , Käs Josef A. , Aktas Bahriye
Published: March 2021

Circulating tumor cells (CTCs) are a potential predictive surrogate marker for disease monitoring. Due to the sparse knowledge about their phenotype and its changes during cancer progression and treatment response, CTC isolation remains challenging. Here we focused on the mechanical characterization of circulating non-hematopoietic cells from breast cancer patients to evaluate its utility for CTC detection. For proof of premise, we used healthy peripheral blood mononuclear cells (PBMCs), human MDA-MB 231 breast cancer cells and human HL-60 leukemia cells to create a CTC model system. For translational experiments CD45 negative cells—possible CTCs—were isolated from blood samples of patients with mamma carcinoma. Cells were mechanically characterized in the optical stretcher (OS). Active and passive cell mechanical data were related with physiological descriptors by a random forest (RF) classifier to identify cell type specific properties. Cancer cells were well distinguishable from PBMC in cell line tests. Analysis of clinical samples revealed that in PBMC the elliptic deformation was significantly increased compared to non-hematopoietic cells. Interestingly, non-hematopoietic cells showed significantly higher shape restoration. Based on Kelvin–Voigt modeling, the RF algorithm revealed that elliptic deformation and shape restoration were crucial parameters and that the OS discriminated non-hematopoietic cells from PBMC with an accuracy of 0.69, a sensitivity of 0.74, and specificity of 0.63. The CD45 negative cell population in the blood of breast cancer patients is mechanically distinguishable from healthy PBMC. Together with cell morphology, the mechanical fingerprint might be an appropriate tool for marker-free CTC detection.
Clinical Utility of Next-Generation Sequencing-Based Panel Testing under the Universal Health-Care System in Japan: A Retrospective Analysis at a Single University Hospital
Authors: Inagaki Chiaki , Maeda Daichi , Hatake Kazue , Sato Yuki , Hashimoto Kae , Sakai Daisuke , Yachida Shinichi , Nonomura Norio , Satoh Taroh
Published: March 2021

Next-generation sequencing (NGS) assay is part of routine care in Japan owing to its reimbursement by Japan’s universal health-care system; however, reimbursement is limited to patients who finished standard treatment. We retrospectively investigated 221 patients who underwent Foundation One CDX (F1CDx) at our hospital. Every F1CDx result was assessed at the molecular tumor board (MTB) for treatment recommendation. Based on patients’ preferences, presumed germline findings were also assessed at the MTB and disclosed at the clinic. In total, 204 patients underwent F1CDx and 195 patients completed the analysis; however, 13.8% of them could not receive the report due to disease progression. Among 168 patients who received the results, 41.6% had at least one actionable alteration, and 3.6% received genomically matched treatment. Presumed germline findings were nominated in 24 patients, and 16.7% of them contacted a geneticist counselor. The NGS assay should be performed earlier in the clinical course to maximize the clinical benefit. Broader reimbursement for the NGS assay would enhance the delivery of precision oncology to patients. Access to clinical trials affects the number of patients who benefit from NGS. Additionally, the disclosure of presumed germline findings is feasible in clinical practice.
Nanocomposite Cathode Catalysts Containing Platinum Deposited on Carbon Nanotubes Modified by O, N, and P Atoms
Authors: Bogdanovskaya Vera , Vernigor Inna , Radina Marina , Andreev Vladimir , Korchagin Oleg
Published: March 2021

Platinum deposited on dispersed materials has so far been the most demanded catalyst for creating cathodes for a wide range of electrochemical power sources. This paper sets out to investigate the effect of carbon nanotube (CNT) modification by O, N, and P atoms on the structural, electrocatalytic, and corrosion properties of the as-synthesized monoplatinum catalysts. The investigated Pt/CNTmod catalysts showed an increased electrochemically active platinum surface area and electrical conductivity, as well as an increased catalytic activity in the oxygen reduction reaction (ORR) in alkaline electrolytes. The improved characteristics of Pt/CNT catalysts are explained by alterations in the composition and number of groups, which are formed on the CNT surface, and their electronic structure. By the sum of the main characteristics, Pt/CNTHNO3+N and Pt/CNTHNO3+NP are the most promising catalysts for use as cathode materials in alkaline media.
An Analysis of the Neurological and Molecular Alterations Underlying the Pathogenesis of Alzheimer’s Disease
Authors: Vidal Chantal , Zhang Li
Published: March 2021

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid beta (Aβ) plaques, neurofibrillary tangles, and neuronal loss. Unfortunately, despite decades of studies being performed on these histological alterations, there is no effective treatment or cure for AD. Identifying the molecular characteristics of the disease is imperative to understanding the pathogenesis of AD. Furthermore, uncovering the key causative alterations of AD can be valuable in developing models for AD treatment. Several alterations have been implicated in driving this disease, including blood–brain barrier dysfunction, hypoxia, mitochondrial dysfunction, oxidative stress, glucose hypometabolism, and altered heme homeostasis. Although these alterations have all been associated with the progression of AD, the root cause of AD has not been identified. Intriguingly, recent studies have pinpointed dysfunctional heme metabolism as a culprit of the development of AD. Heme has been shown to be central in neuronal function, mitochondrial respiration, and oxidative stress. Therefore, dysregulation of heme homeostasis may play a pivotal role in the manifestation of AD and its various alterations. This review will discuss the most common neurological and molecular alterations associated with AD and point out the critical role heme plays in the development of this disease.
Involvement of the Catecholamine Pathway in Glioblastoma Development
Authors: Kraboth Zoltán , Kajtár Bela , Gálik Bence , Gyenesei Attila , Miseta Attila , Kalman Bernadette
Published: March 2021

Glioblastoma (GBM) is the most aggressive tumor of the central nervous system (CNS). The standard of care improves the overall survival of patients only by a few months. Explorations of new therapeutic targets related to molecular properties of the tumor are under way. Even though neurotransmitters and their receptors normally function as mediators of interneuronal communication, growing data suggest that these molecules are also involved in modulating the development and growth of GBM by acting on neuronal and glioblastoma stem cells. In our previous DNA CpG methylation studies, gene ontology analyses revealed the involvement of the monoamine pathway in sequential GBM. In this follow-up study, we quantitated the expression levels of four selected catecholamine pathway markers (alpha 1D adrenergic receptor—ADRA1D; adrenergic beta receptor kinase 1 or G protein-coupled receptor kinase 2—ADRBK1/GRK2; dopamine receptor D2—DRD2; and synaptic vesicle monoamine transporter—SLC18A2) by immunohistochemistry, and compared the histological scores with the methylation levels within the promoters + genes of these markers in 21 pairs of sequential GBM and in controls. Subsequently, we also determined the promoter and gene methylation levels of the same markers in an independent database cohort of sequential GBM pairs. These analyses revealed partial inverse correlations between the catecholamine protein expression and promoter + gene methylation levels, when the tumor and control samples were compared. However, we found no differences in the promoter + gene methylation levels of these markers in either our own or in the database primary–recurrent GBM pairs, despite the higher protein expression of all markers in the primary samples. This observation suggests that regulation of catecholamine expression is only partially related to CpG methylation within the promoter + gene regions, and additional mechanisms may also influence the expression of these markers in progressive GBM. These analyses underscore the involvement of certain catecholamine pathway markers in GBM development and suggest that these molecules mediating or modulating tumor growth merit further exploration.
Biomechanics of Ex Vivo-Generated Red Blood Cells Investigated by Optical Tweezers and Digital Holographic Microscopy
Authors: Bernecker Claudia , Lima Maria Augusta R. B. F. , Ciubotaru Catalin D. , Schlenke Peter , Dorn Isabel , Cojoc Dan
Published: March 2021

Ex vivo-generated red blood cells are a promising resource for future safe blood products, manufactured independently of voluntary blood donations. The physiological process of terminal maturation from spheroid reticulocytes to biconcave erythrocytes has not been accomplished yet. A better biomechanical characterization of cultured red blood cells (cRBCs) will be of utmost interest for manufacturer approval and therapeutic application. Here, we introduce a novel optical tweezer (OT) approach to measure the deformation and elasticity of single cells trapped away from the coverslip. To investigate membrane properties dependent on membrane lipid content, two culture conditions of cRBCs were investigated, cRBCPlasma with plasma and cRBCHPL supplemented with human platelet lysate. Biomechanical characterization of cells under optical forces proves the similar features of native RBCs and cRBCHPL, and different characteristics for cRBCPlasma. To confirm these results, we also applied a second technique, digital holographic microscopy (DHM), for cells laid on the surface. OT and DHM provided related results in terms of cell deformation and membrane fluctuations, allowing a reliable discrimination between cultured and native red blood cells. The two techniques are compared and discussed in terms of application and complementarity.
Historical Perspective of the G Protein-Coupled Receptor Kinase Family
Authors: Benovic Jeffrey L.
Published: March 2021

Agonist activation of G protein-coupled receptors promotes sequential interaction of the receptor with heterotrimeric G proteins, G protein-coupled receptor kinases (GRKs), and arrestins. GRKs play a central role in mediating the switch from G protein to arrestin interaction and thereby control processes such as receptor desensitization and trafficking and arrestin-mediated signaling. In this review, I provide a historical perspective on some of the early studies that identified the family of GRKs with a primary focus on the non-visual GRKs. These studies included identification, purification, and cloning of the β-adrenergic receptor kinase in the mid- to late-1980s and subsequent cloning and characterization of additional members of the GRK family. This helped to lay the groundwork for ensuing work focused on understanding the structure and function of these important enzymes.
Oxidized Phospholipids in Tumor Microenvironment Stimulate Tumor Metastasis via Regulation of Autophagy
Authors: Seok Jin Kyung , Hong Eun-Hee , Yang Gabsik , Lee Hye Eun , Kim Sin-Eun , Liu Kwang-Hyeon , Kang Han Chang , Cho Yong-Yeon , Lee Hye Suk , Lee Joo Young
Published: March 2021

Oxidized phospholipids are well known to play physiological and pathological roles in regulating cellular homeostasis and disease progression. However, their role in cancer metastasis has not been entirely understood. In this study, effects of oxidized phosphatidylcholines such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on epithelial-mesenchymal transition (EMT) and autophagy were determined in cancer cells by immunoblotting and confocal analysis. Metastasis was analyzed by a scratch wound assay and a transwell migration/invasion assay. The concentrations of POVPC and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC) in tumor tissues obtained from patients were measured by LC-MS/MS analysis. POVPC induced EMT, resulting in increase of migration and invasion of human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF7). POVPC induced autophagic flux through AMPK-mTOR pathway. Pharmacological inhibition or siRNA knockdown of autophagy decreased migration and invasion of POVPC-treated HepG2 and MCF7 cells. POVPC and PGPC levels were greatly increased at stage II of patient-derived intrahepatic cholangiocarcinoma tissues. PGPC levels were higher in malignant breast tumor tissues than in adjacent nontumor tissues. The results show that oxidized phosphatidylcholines increase metastatic potential of cancer cells by promoting EMT, mediated through autophagy. These suggest the positive regulatory role of oxidized phospholipids accumulated in tumor microenvironment in the regulation of tumorigenesis and metastasis.
Oligodendrocyte Dysfunction in Amyotrophic Lateral Sclerosis: Mechanisms and Therapeutic Perspectives
Authors: Raffaele Stefano , Boccazzi Marta , Fumagalli Marta
Published: March 2021

Myelin is the lipid-rich structure formed by oligodendrocytes (OLs) that wraps the axons in multilayered sheaths, assuring protection, efficient saltatory signal conduction and metabolic support to neurons. In the last few years, the impact of OL dysfunction and myelin damage has progressively received more attention and is now considered to be a major contributing factor to neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). Upon OL injury, oligodendrocyte precursor cells (OPCs) of adult nervous tissue sustain the generation of new OLs for myelin reconstitution, but this spontaneous regeneration process fails to successfully counteract myelin damage. Of note, the functions of OPCs exceed the formation and repair of myelin, and also involve the trophic support to axons and the capability to exert an immunomodulatory role, which are particularly relevant in the context of neurodegeneration. In this review, we deeply analyze the impact of dysfunctional OLs in ALS pathogenesis. The possible mechanisms underlying OL degeneration, defective OPC maturation, and impairment in energy supply to motor neurons (MNs) have also been examined to provide insights on future therapeutic interventions. On this basis, we discuss the potential therapeutic utility in ALS of several molecules, based on their remyelinating potential or capability to enhance energy metabolism.
Genetic Approaches Using Zebrafish to Study the Microbiota–Gut–Brain Axis in Neurological Disorders
Authors: Lee Jae-Geun , Cho Hyun-Ju , Jeong Yun-Mi , Lee Jeong-Soo
Published: March 2021

The microbiota–gut–brain axis (MGBA) is a bidirectional signaling pathway mediating the interaction of the microbiota, the intestine, and the central nervous system. While the MGBA plays a pivotal role in normal development and physiology of the nervous and gastrointestinal system of the host, its dysfunction has been strongly implicated in neurological disorders, where intestinal dysbiosis and derived metabolites cause barrier permeability defects and elicit local inflammation of the gastrointestinal tract, concomitant with increased pro-inflammatory cytokines, mobilization and infiltration of immune cells into the brain, and the dysregulated activation of the vagus nerve, culminating in neuroinflammation and neuronal dysfunction of the brain and behavioral abnormalities. In this topical review, we summarize recent findings in human and animal models regarding the roles of the MGBA in physiological and neuropathological conditions, and discuss the molecular, genetic, and neurobehavioral characteristics of zebrafish as an animal model to study the MGBA. The exploitation of zebrafish as an amenable genetic model combined with in vivo imaging capabilities and gnotobiotic approaches at the whole organism level may reveal novel mechanistic insights into microbiota–gut–brain interactions, especially in the context of neurological disorders such as autism spectrum disorder and Alzheimer’s disease.