bluuebunny/crossref_metadata_2025 huggingface dataset:
HER2 Expression in Circulating Tumour Cells Isolated from Metastatic Breast Cancer Patients Using a Size-Based Microfluidic Device
Authors: Lopes Cláudia , Piairo Paulina , Chícharo Alexandre , Abalde-Cela Sara , Pires Liliana R. , Corredeira Patrícia , Alves Patrícia , Muinelo-Romay Laura , Costa Luís , Diéguez Lorena
Published: September 2021

HER2 is a prognostic and predictive biomarker in breast cancer, normally assessed in tumour biopsy and used to guide treatment choices. Circulating tumour cells (CTCs) escape the primary tumour and enter the bloodstream, exhibiting great metastatic potential and representing a real-time snapshot of the tumour burden. Liquid biopsy offers the unique opportunity for low invasive sampling in cancer patients and holds the potential to provide valuable information for the clinical management of cancer patients. This study assesses the performance of the RUBYchip™, a microfluidic system for CTC capture based on cell size and deformability, and compares it with the only FDA-approved technology for CTC enumeration, CellSearch®. After optimising device performance, 30 whole blood samples from metastatic breast cancer patients were processed with both technologies. The expression of HER2 was assessed in isolated CTCs and compared to tissue biopsy. Results show that the RUBYchipTM was able to isolate CTCs with higher efficiency than CellSearch®, up to 10 times more, averaging all samples. An accurate evaluation of different CTC subpopulations, including HER2+ CTCs, was provided. Liquid biopsy through the use of the RUBYchipTM in the clinic can overcome the limitations of histological testing and evaluate HER2 status in patients in real-time, helping to tailor treatment during disease evolution.
A Truncated NRIP1 Mutant Amplifies Microsatellite Instability of Colorectal Cancer by Regulating MSH2/MSH6 Expression, and Is a Prognostic Marker of Stage III Tumors
Authors: Palassin Pascale , Lapierre Marion , Pyrdziak Samuel , Wagner Antoine , Stehle Régine , Corsini Carole , Duffour Jacqueline , Bonnet Sandrine , Boulahtouf Abdelhay , Rodriguez Carmen , Ho-Pun-Cheung Alexandre , Lopez-Crapez Evelyne , Boissière-Michot Florence , Bibeau Frédéric , Thezenas Simon , Elarouci Nabila , Selves Janick , Hoffmann Jean-Sébastien , Roepman Paul , Mazard Thibault , Buhard Olivier , Duval Alex , Jalaguier Stéphan , Cavaillès Vincent , Castet-Nicolas Audrey
Published: September 2021

Microsatellite instability (MSI) is related to the alteration of mismatch repair (MMR) genes and plays a key role in colorectal cancer (CRC) pathogenesis. We previously reported that the transcription factor Nuclear Receptor Interacting Protein 1 (NRIP1) is involved in sporadic intestinal tumorigenesis. The aim of this study was to decipher its role in MSI CRC. By using different mouse models and engineered cell lines, we demonstrated that NRIP1 increased MSH2 and MSH6 MMR gene transcription and mRNA/protein levels. In human CRC cells, NRIP1 expression was associated with decreased MSI and the hypermutator phenotype, and with resistance to chemotherapy drugs. Using a cohort of 194 CRC patients, we detected in 22% of the cases a MSI-induced frameshift mutation in the NRIP1 coding sequence. This genetic alteration generates a truncated protein with a dominant negative activity that increased human CRC cell proliferation and impaired the regulation of MSH2 and MSH6 gene expression. Moreover, the NRIP1 mutant correlated with a decreased overall survival of patients with advanced CRC, especially when MLH1-deficient. By decreasing the expression of MSH2 and MSH6 gene expression, the NRIP1 variant may amplify MLH1-dependent CRC progression and behave as a new prognostic marker of advanced MSI CRC.
Insights from IgE Immune Surveillance in Allergy and Cancer for Anti-Tumour IgE Treatments
Authors: McCraw Alex J. , Chauhan Jitesh , Bax Heather J. , Stavraka Chara , Osborn Gabriel , Grandits Melanie , López-Abente Jacobo , Josephs Debra H. , Spicer James , Wagner Gerd K. , Karagiannis Sophia N. , Chenoweth Alicia , Crescioli Silvia
Published: September 2021

IgE, the predominant antibody class of the allergic response, is known for its roles in protecting against parasites; however, a growing body of evidence indicates a significant role for IgE and its associated effector cells in tumour immunosurveillance, highlighted by the field of AllergoOncology and the successes of the first-in-class IgE cancer therapeutic MOv18. Supporting this concept, substantial epidemiological data ascribe potential roles for IgE, allergy, and atopy in protecting against specific tumour types, with a corresponding increased cancer risk associated with IgE immunodeficiency. Here, we consider how epidemiological data in combination with functional data reveals a complex interplay of IgE and allergy with cancer, which cannot be explained solely by one of the existing conventional hypotheses. We furthermore discuss how, in turn, such data may be used to inform future therapeutic approaches, including the clinical management of different patient groups. With epidemiological findings highlighting several high-risk cancer types protected against by high IgE levels, it is possible that use of IgE-based therapeutics for a range of malignant indications may offer efficacy to complement that of established IgG-class antibodies.
Treatment Strategies for High-Risk Localized and Locally Advanced and Oligometastatic Prostate Cancer
Authors: Makino Tomoyuki , Izumi Kouji , Iwamoto Hiroaki , Mizokami Atsushi
Published: September 2021

Despite the significant advances in the treatment of high-risk prostate cancer, patients with very high-risk features such as being locally advanced (clinical stage T3–4 or minimal nodal involvement), having a high Gleason pattern, or with oligometastasis may still have a poor prognosis despite aggressive treatment. Multidisciplinary treatment with both local and systemic therapies is thought to be effective, however, unfortunately, there is still no standard treatment. However, in recent years, local definitive therapy using a combination of radiotherapy and androgen deprivation is being supported by several randomized clinical trials. This study reviews the current literature with a focus on the definition of very high-risk prostate cancer, the role of modern imaging, and its treatment options.
The Hidden Treasures of Preoperative Blood Assessment in Oral Cancer: A Potential Source of Biomarkers
Authors: Caruntu Ana , Moraru Liliana , Lupu Mihai , Taubner Lacramioara , Caruntu Constantin , Tanase Cristiana
Published: September 2021

(1) Background: Oral squamous cell carcinoma (OSCC) is a common malignancy, and the impact of immune and inflammatory mechanisms in its development and progression are of major interest. The aim of our study is to assess the prognostic potential of circulating immune and inflammatory elements determined preoperatively in patients with OSCC, as well as the development of a new compound parameter with predictive value. (2) Methods: We assessed preoperative fibrinogen (Fib) and the platelet-to-lymphocyte ratio (PLR) in 111 OSCC patients. Using a mathematic algorithm, we determined a composite parameter with cumulative information from Fib and PLR, named Fibrinogen-PLR Algorithm (FiPLA). Survival analysis, followed by bivariate and multivariate analyses, was subsequently conducted. (3) Results: Increased preoperative Fib and PLR levels were associated with poor outcome in OSCC (p = 0.0001 and p = 0.0015, respectively). Preoperative FiPLA values were also associated with poor patient survival (p < 0.0001). Multivariate analysis confirmed the independent prognostic role for FiPLA only (CI95% 1.232–67.770, p = 0.03), showing the superior predictive value of FiPLA compared to its individual components. (4) Conclusions: Preoperative assessments of circulating immune and inflammatory elements can provide high-quality prognostic information, and they represent valuable tools in clinical practice, facilitating the early risk stratification of patients with OSCC.
Targeting CD82/KAI1 for Precision Therapeutics in Surmounting Metastatic Potential in Breast Cancer
Authors: Viera Maximillian , Yip George Wai Cheong , Shen Han-Ming , Baeg Gyeong Hun , Bay Boon Huat
Published: September 2021

Metastasis is the main cause of mortality in breast cancer patients. There is an unmet need to develop therapies that can impede metastatic spread. Precision oncology has shown great promise for the treatment of cancers, as the therapeutic approach is tailored to a specific group of patients who are likely to benefit from the treatment, rather than the traditional approach of “one size fits all”. CD82, also known as KAI1, a glycoprotein belonging to the tetraspanin family and an established metastasis suppressor, could potentially be exploited to hinder metastases in breast cancer. This review explores the prospect of targeting CD82 as an innovative therapeutic approach in precision medicine for breast cancer patients, with the goal of preventing cancer progression and metastasis. Such an approach would entail the selection of a subset of breast cancer patients with low levels of CD82, and instituting an appropriate treatment scheme tailored towards restoring the levels of CD82 in this group of patients. Proposed precision treatment regimens include current modalities of treating breast cancer, in combination with either clinically approved drugs that could restore the levels of CD82, CD82 peptide mimics or non-coding RNA-based therapeutics.
Organ-Chip Models: Opportunities for Precision Medicine in Pancreatic Cancer
Authors: Haque Muhammad R. , Rempert Trevor H. , Al-Hilal Taslim A. , Wang Chengyao , Bhushan Abhinav , Bishehsari Faraz
Published: September 2021

Pancreatic Ductal Adenocarcinoma (PDAC) is an expeditiously fatal malignancy with a five-year survival rate of 6–8%. Conventional chemotherapeutics fail in many cases due to inadequate primary response and rapidly developing resistance. This treatment failure is particularly challenging in pancreatic cancer because of the high molecular heterogeneity across tumors. Additionally, a rich fibro-inflammatory component within the tumor microenvironment (TME) limits the delivery and effectiveness of anticancer drugs, further contributing to the lack of response or developing resistance to conventional approaches in this cancer. As a result, there is an urgent need to model pancreatic cancer ex vivo to discover effective drug regimens, including those targeting the components of the TME on an individualized basis. Patient-derived three-dimensional (3D) organoid technology has provided a unique opportunity to study patient-specific cancerous epithelium. Patient-derived organoids cultured with the TME components can more accurately reflect the in vivo tumor environment. Here we present the advances in organoid technology and multicellular platforms that could allow for the development of “organ-on-a-chip” approaches to recapitulate the complex cellular interactions in PDAC tumors. We highlight the current advances of the organ-on-a-chip-based cancer models and discuss their potential for the preclinical selection of individualized treatment in PDAC.
Role of Metastasis-Related microRNAs in Prostate Cancer Progression and Treatment
Authors: Oh-Hohenhorst Su Jung , Lange Tobias
Published: September 2021

Prostate cancer (PCa) is one of the most prevalent cancer types in males and the consequences of its distant metastatic deposits are the leading cause of PCa mortality. Therefore, identifying the causes and molecular mechanisms of hematogenous metastasis formation is of considerable clinical importance for the future development of improved therapeutic approaches. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level by targeting messenger RNAs. Numerous studies have identified miRNAs as promotors or inhibitors of metastasis and revealed, in part, their targeting pathways in PCa. Because miRNAs are remarkably stable and can be detected in both tissue and body fluid, its potential as specific biomarkers for metastasis and therapeutic response is also currently under preclinical evaluation. In the present review, we focus on miRNAs that are supposed to initiate or suppress metastasis by targeting several key mRNAs in PCa. Metastasis-suppressing miRNAs include miR-33a-5p, miR-34, miR-132 and miR-212, miR-145, the miR-200 family (incl. miR-141-3p), miR-204-5p, miR-532-3p, miR-335, miR-543, miR-505-3p, miR 19a 3p, miR-802, miR-940, and miR-3622a. Metastasis-promoting RNAs, such as miR-9, miR-181a, miR-210-3, miR-454, miR-671-5p, have been shown to increase the metastatic potential of PCa cells. Other metastasis-related miRNAs with conflicting reports in the literature are also discussed (miR-21 and miR-186). Finally, we summarize the recent developments of miRNA-based therapeutic approaches, as well as current limitations in PCa. Taken together, the metastasis-controlling miRNAs provide the potential to be integrated in the strategy of diagnosis, prognosis, and treatment of metastatic PCa. Nevertheless, there is still a lack of consistency between certain miRNA signatures and reproducibility, which impedes clinical implementation.
Perspectives on Mitochondria–ER and Mitochondria–Lipid Droplet Contact in Hepatocytes and Hepatic Lipid Metabolism
Authors: Ma Xiaowen , Qian Hui , Chen Allen , Ni Hong-Min , Ding Wen-Xing
Published: September 2021

Emerging evidence suggests that mitochondrion–endoplasmic reticulum (ER) and mitochondrion–lipid droplet (LD) contact sites are critical in regulating lipid metabolism in cells. It is well established that intracellular organelles communicate with each other continuously through membrane contact sites to maintain organelle function and cellular homeostasis. The accumulation of LDs in hepatocytes is an early indicator of non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), which may indicate a breakdown in proper inter-organelle communication. In this review, we discuss previous findings in mitochondrion–ER and mitochondrion–LD contact, focusing on their roles in lipid metabolism in hepatocytes. We also present evidence of a unique mitochondrion–LD contact structure in hepatocytes under various physiological and pathological conditions and propose a working hypothesis to speculate about the role of these structures in regulating the functions of mitochondria and LDs and their implications in NAFLD and ALD.
Alpha-Linolenic Acid Impedes Cadmium-Induced Oxidative Stress, Neuroinflammation, and Neurodegeneration in Mouse Brain
Authors: Alam Sayed-Ibrar , Kim Min-Woo , Shah Fawad Ali , Saeed Kamran , Ullah Rahat , Kim Myeong-Ok
Published: September 2021

Alpha-Linolenic acid (ALA), an omega-3 polyunsaturated fatty acid, is extracted from plant sources and has been shown to be one of the anti-inflammatory and antioxidant agents. Herein, we revealed the molecular mechanism underlying the anti-inflammatory and antioxidant potential of (ALA), against cadmium in the adult mouse brain. We evaluated the neuroprotective effect of ALA (60 mg/kg per oral for 6 weeks) against CdCl2 (5 mg/kg)-induced oxidative stress, neuroinflammation, and neuronal apoptosis. According to our findings, ALA markedly reduced ROS production and nitric oxide synthase 2 (NOS2) and enhanced the expression of nuclear factor-2 erythroid-2 (Nrf-2) and heme oxygenase-1 (HO-1) in mice treated with CdCl2. Most importantly, the molecular docking study revealed that ALA allosterically decreases the overexpression of c-Jun N-terminal kinase (JNK) activity and inhibited the detrimental effect against CdCl2. Moreover, ALA suppressed CdCl2-induced glial fibrillary acidic protein (GFAP), nuclear factor-kappa b (NF-κB), and interleukin-1β (IL-1β) in the mouse brain. Further, we also checked the pro- and anti-apoptotic proteins markers such as Bax, Bcl-2, and caspase-3, which were regulated in the cortex of ALA co-treated mouse brain. Overall, our study suggests that oral administration of ALA can impede oxidative stress, neuroinflammation, and increase neuronal apoptosis in the cortex of Cd-injected mouse brain.
P2X Receptor-Dependent Modulation of Mast Cell and Glial Cell Activities in Neuroinflammation
Authors: Salcman Barbora , Affleck Karen , Bulfone-Paus Silvia
Published: September 2021

Localisation of mast cells (MCs) at the abluminal side of blood vessels in the brain favours their interaction with glial cells, neurons, and endothelial cells, resulting in the activation of these cells and the release of pro-inflammatory mediators. In turn, stimulation of glial cells, such as microglia, astrocytes, and oligodendrocytes may result in the modulation of MC activities. MCs, microglia, astrocytes, and oligodendrocytes all express P2X receptors (P2XRs) family members that are selectively engaged by ATP. As increased concentrations of extracellular adenosine 5′-triphosphate (ATP) are present in the brain in neuropathological conditions, P2XR activation in MCs and glial cells contributes to the control of their communication and amplification of the inflammatory response. In this review we discuss P2XR-mediated MC activation, its bi-directional effect on microglia, astrocytes and oligodendrocytes and role in neuroinflammation.
Substrate Reduction Therapy Reverses Mitochondrial, mTOR, and Autophagy Alterations in a Cell Model of Gaucher Disease
Authors: Peng Yanyan , Liou Benjamin , Lin Yi , Fannin Venette , Zhang Wujuan , Feldman Ricardo A. , Setchell Kenneth D. R. , Grabowski Gregory A. , Sun Ying
Published: September 2021

Substrate reduction therapy (SRT) in clinic adequately manages the visceral manifestations in Gaucher disease (GD) but has no direct effect on brain disease. To understand the molecular basis of SRT in GD treatment, we evaluated the efficacy and underlying mechanism of SRT in an immortalized neuronal cell line derived from a Gba knockout (Gba-/-) mouse model. Gba-/- neurons accumulated substrates, glucosylceramide, and glucosylsphingosine. Reduced cell proliferation was associated with altered lysosomes and autophagy, decreased mitochondrial function, and activation of the mTORC1 pathway. Treatment of the Gba-/- neurons with venglustat analogue GZ452, a central nervous system-accessible SRT, normalized glucosylceramide levels in these neurons and their isolated mitochondria. Enlarged lysosomes were reduced in the treated Gba-/- neurons, accompanied by decreased autophagic vacuoles. GZ452 treatment improved mitochondrial membrane potential and oxygen consumption rate. Furthermore, GZ452 diminished hyperactivity of selected proteins in the mTORC1 pathway and improved cell proliferation of Gba-/- neurons. These findings reinforce the detrimental effects of substrate accumulation on mitochondria, autophagy, and mTOR in neurons. A novel rescuing mechanism of SRT was revealed on the function of mitochondrial and autophagy–lysosomal pathways in GD. These results point to mitochondria and the mTORC1 complex as potential therapeutic targets for treatment of GD.
Comprehensive Characterization of Multitissue Expression Landscape, Co-Expression Networks and Positive Selection in Pikeperch
Authors: Nguinkal Julien , Verleih Marieke , de los Ríos-Pérez Lidia , Brunner Ronald , Sahm Arne , Bej Saptarshi , Rebl Alexander , Goldammer Tom
Published: September 2021

Promising efforts are ongoing to extend genomics resources for pikeperch (Sander lucioperca), a species of high interest for the sustainable European aquaculture sector. Although previous work, including reference genome assembly, transcriptome sequence, and single-nucleotide polymorphism genotyping, added a great wealth of genomic tools, a comprehensive characterization of gene expression across major tissues in pikeperch still remains an unmet research need. Here, we used deep RNA-Sequencing of ten vital tissues collected in eight animals to build a high-confident and annotated transcriptome atlas, to detect the tissue-specificity of gene expression and co-expression network modules, and to investigate genome-wide selective signatures in the Percidae fish family. Pathway enrichment and protein–protein interaction network analyses were performed to characterize the unique biological functions of tissue-specific genes and co-expression modules. We detected strong functional correlations and similarities of tissues with respect to their expression patterns—but also significant differences in the complexity and composition of their transcriptomes. Moreover, functional analyses revealed that tissue-specific genes essentially play key roles in the specific physiological functions of the respective tissues. Identified network modules were also functionally coherent with tissues’ main physiological functions. Although tissue specificity was not associated with positive selection, several genes under selection were found to be involved in hypoxia, immunity, and gene regulation processes, that are crucial for fish adaption and welfare. Overall, these new resources and insights will not only enhance the understanding of mechanisms of organ biology in pikeperch, but also complement the amount of genomic resources for this commercial species.
Nogo-A Modulates the Synaptic Excitation of Hippocampal Neurons in a Ca2+-Dependent Manner
Authors: Metzdorf Kristin , Fricke Steffen , Balia Maria Teresa , Korte Martin , Zagrebelsky Marta
Published: September 2021

A tight regulation of the balance between inhibitory and excitatory synaptic transmission is a prerequisite for synaptic plasticity in neuronal networks. In this context, the neurite growth inhibitor membrane protein Nogo-A modulates synaptic plasticity, strength, and neurotransmitter receptor dynamics. However, the molecular mechanisms underlying these actions are unknown. We show that Nogo-A loss-of-function in primary mouse hippocampal cultures by application of a function-blocking antibody leads to higher excitation following a decrease in GABAARs at inhibitory and an increase in the GluA1, but not GluA2 AMPAR subunit at excitatory synapses. This unbalanced regulation of AMPAR subunits results in the incorporation of Ca2+-permeable GluA2-lacking AMPARs and increased intracellular Ca2+ levels due to a higher Ca2+ influx without affecting its release from the internal stores. Increased neuronal activation upon Nogo-A loss-of-function prompts the phosphorylation of the transcription factor CREB and the expression of c-Fos. These results contribute to the understanding of the molecular mechanisms underlying the regulation of the excitation/inhibition balance and thereby of plasticity in the brain.
Differential Expression Pattern of Goat Uterine Fluids Extracellular Vesicles miRNAs during Peri-Implantation
Authors: Xie Yanshe , Liu Guangbin , Zang Xupeng , Hu Qun , Zhou Chen , Li Yaokun , Liu Dewu , Hong Linjun
Published: September 2021

Early pregnancy failure occurs when a mature embryo attaches to an unreceptive endometrium. During the formation of a receptive endometrium, extracellular vesicles (EVs) of the uterine fluids (UFs) deliver regulatory molecules such as small RNAs to mediate intrauterine communication between the embryo and the endometrium. However, profiling of small RNAs in goat UFs’ EVs during pregnancy recognition (day 16) has not been carried out. In this study, EVs were isolated from UFs on day 16 of the estrous cycle or gestation. They were isolated by Optiprep™ Density G radient (ODG) and verified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting. Immunostaining demonstrated that CD63 was present both in the endometrial epithelium and glandular epithelium, and stain intensity was greater in the pregnant endometrium compared to the non-pregnant endometrium. Small RNA sequencing revealed that UFs’ EVs contained numerous sRNA families and a total of 106 differentially expressed miRNAs (DEMs). Additionally, 1867 target genes of the DEMs were obtained, and miRNA–mRNA interaction networks were constructed. GO and KEGG analysis showed that miRNAs were significantly associated with the formation of a receptive endometrium and embryo implantation. In addition, the fluorescence in situ hybridization assay (FISH) showed that chi-miR-451-5p was mainly expressed in stromal cells of the endometrium and a higher level was detected in the endometrial luminal epithelium in pregnant states. Moreover, the dual-luciferase reporter assay showed that chi-miR-451-5p directly binds to PSMB8 and may play an important role in the formation of a receptive endometrium and embryo implantation. In conclusion, these results reveal that UFs’ EVs contain various small RNAs that may be vital in the formation of a receptive endometrium and embryo implantation.
Specificity and Redundancy of Profilin 1 and 2 Function in Brain Development and Neuronal Structure
Authors: Di Domenico Marina , Jokwitz Melanie , Witke Walter , Pilo Boyl Pietro
Published: September 2021

Profilin functions have been discussed in numerous cellular processes, including actin polymerization. One puzzling aspect is the concomitant expression of more than one profilin isoform in most tissues. In neuronal precursors and in neurons, profilin 1 and profilin 2 are co-expressed, but their specific and redundant functions in brain morphogenesis are still unclear. Using a conditional knockout mouse model to inactivate both profilins in the developing CNS, we found that threshold levels of profilin are necessary for the maintenance of the neuronal stem-cell compartment and the generation of the differentiated neurons, irrespective of the specific isoform. During embryonic development, profilin 1 is more abundant than profilin 2; consequently, modulation of profilin 1 levels resulted in a more severe phenotype than depletion of profilin 2. Interestingly, the relevance of the isoforms was reversed in the postnatal brain. Morphology of mature neurons showed a stronger dependence on profilin 2, since this is the predominant isoform in neurons. Our data highlight redundant functions of profilins in neuronal precursor expansion and differentiation, as well as in the maintenance of pyramidal neuron dendritic arborization. The specific profilin isoform is less relevant; however, a threshold profilin level is essential. We propose that the common activity of profilin 1 and profilin 2 in actin dynamics is responsible for the observed compensatory effects.
Epigenetic Dysregulation of Mammalian Male Meiosis Caused by Interference of Recombination and Synapsis
Authors: de la Fuente Roberto , Pratto Florencia , Hernández-Hernández Abrahan , Manterola Marcia , López-Jiménez Pablo , Gómez Rocío , Viera Alberto , Parra María Teresa , Kouznetsova Anna , Camerini-Otero R. Daniel , Page Jesús
Published: September 2021

Meiosis involves a series of specific chromosome events, namely homologous synapsis, recombination, and segregation. Disruption of either recombination or synapsis in mammals results in the interruption of meiosis progression during the first meiotic prophase. This is usually accompanied by a defective transcriptional inactivation of the X and Y chromosomes, which triggers a meiosis breakdown in many mutant models. However, epigenetic changes and transcriptional regulation are also expected to affect autosomes. In this work, we studied the dynamics of epigenetic markers related to chromatin silencing, transcriptional regulation, and meiotic sex chromosome inactivation throughout meiosis in knockout mice for genes encoding for recombination proteins SPO11, DMC1, HOP2 and MLH1, and the synaptonemal complex proteins SYCP1 and SYCP3. These models are defective in recombination and/or synapsis and promote apoptosis at different stages of progression. Our results indicate that impairment of recombination and synapsis alter the dynamics and localization pattern of epigenetic marks, as well as the transcriptional regulation of both autosomes and sex chromosomes throughout prophase-I progression. We also observed that the morphological progression of spermatocytes throughout meiosis and the dynamics of epigenetic marks are processes that can be desynchronized upon synapsis or recombination alteration. Moreover, we detected an overlap of early and late epigenetic signatures in most mutants, indicating that the normal epigenetic transitions are disrupted. This can alter the transcriptional shift that occurs in spermatocytes in mid prophase-I and suggest that the epigenetic regulation of sex chromosomes, but also of autosomes, is an important factor in the impairment of meiosis progression in mammals.
The Endothelial Landscape and Its Role in Von Hippel–Lindau Disease
Authors: de Rojas-P Isabel , Albiñana Virginia , Taranets Lyudmyla , Recio-Poveda Lucía , Cuesta Angel M. , Popov Nikita , Kronenberger Thales , Botella Luisa M.
Published: September 2021

Von Hippel–Lindau disease (VHL) is a rare hereditary disease characterized by the predisposal to develop different types of highly vascularized tumors. VHL patients carry a VHL mutation that causes partial lack of functional VHL protein (pVHL) in all cells, and a total lack thereof in cells harboring a second hit mutation. Absence of pVHL generates a prolonged state of pseudo-hypoxia in the cell due to accumulation of hypoxia inducible factor, an important transcription factor regulating pro-tumorigenic genes. The work here presented focuses on characterizing the endothelium of VHL patients, by means of blood outgrowth endothelial cells (BOECs). Transcriptome analysis of VHL-derived BOECs, further supported by in vitro assays, shows that these cells are at a disadvantage, as evidenced by loss of cell adhesion capacity, angiogenesis defects, and immune response and oxidative metabolic gene downregulation, which induce oxidative stress. These results suggest that the endothelium of VHL patients is functionally compromised and more susceptible to tumor development. These findings contribute to shedding light on the vascular landscape of VHL patients preceding the second hit mutation in the VHL gene. This knowledge could be useful in searching for new therapies for these patients and other vascular diseases.
Estradiol Inhibits Human Brain Vascular Pericyte Migration Activity: A Functional and Transcriptomic Analysis
Authors: Kurmann Lisa , Okoniewski Michal , Dubey Raghvendra K.
Published: September 2021

Stroke is the third leading cause of mortality in women and it kills twice as many women as breast cancer. A key role in the pathophysiology of stroke plays the disruption of the blood–brain barrier (BBB) within the neurovascular unit. While estrogen induces vascular protective actions, its influence on stroke remains unclear. Moreover, experiments assessing its impact on endothelial cells to induce barrier integrity are non-conclusive. Since pericytes play an active role in regulating BBB integrity and function, we hypothesize that estradiol may influence BBB by regulating their activity. In this study using human brain vascular pericytes (HBVPs) we investigated the impact of estradiol on key pericyte functions known to influence BBB integrity. HBVPs expressed estrogen receptors (ER-α, ER-β and GPER) and treatment with estradiol (10 nM) inhibited basal cell migration but not proliferation. Since pericyte migration is a hallmark for BBB disruption following injury, infection and inflammation, we investigated the effects of estradiol on TNFα-induced PC migration. Importantly, estradiol prevented TNFα-induced pericyte migration and this effect was mimicked by PPT (ER-α agonist) and DPN (ER-β agonist), but not by G1 (GPR30 agonist). The modulatory effects of estradiol were abrogated by MPP and PHTPP, selective ER-α and ER-β antagonists, respectively, confirming the role of ER-α and ER-β in mediating the anti-migratory actions of estrogen. To delineate the intracellular mechanisms mediating the inhibitory actions of estradiol on PC migration, we investigated the role of AKT and MAPK activation. While estradiol consistently reduced the TNFα-induced MAPK and Akt phosphorylation, only the inhibition of MAPK, but not Akt, significantly abrogated the migratory actions of TNFα. In transendothelial electrical resistance measurements, estradiol induced barrier function (TEER) in human brain microvascular endothelial cells co-cultured with pericytes, but not in HBMECs cultured alone. Importantly, transcriptomics analysis of genes modulated by estradiol in pericytes showed downregulation of genes known to increase cell migration and upregulation of genes known to inhibit cell migration. Taken together, our findings provide the first evidence that estradiol modulates pericyte activity and thereby improves endothelial integrity.
Assessment of Sleep-Related Problems in Children with Cerebral Palsy Using the SNAKE Sleep Questionnaire
Authors: Dreier Larissa Alice , Kapanci Tugba , Lonnemann Katharina , Koch-Hogrebe Margarete , Wiethoff-Ubrig Lucia , Rauchenzauner Markus , Blankenburg Markus , Zernikow Boris , Wager Julia , Rostasy Kevin
Published: September 2021

Cerebral palsy (CP) represents the most common motor impairment in childhood. The presence of sleep problems has not yet been investigated with an instrument specifically designed for this population. In this hospital-based, prospective study, N = 100 children (M = 7.9, range: 2–18 years) with CP were included. All patients underwent pediatric neurologists’ screening incorporating instruments (Data Collection Form; Gross Motor Functions Classification System, GMFCS; Bimanual Fine Motor Function, BFMF) recommended by the “Surveillance of Cerebral Palsy in Europe (SCPE)”. Parents completed the “Sleep Questionnaire for Children with Severe Psychomotor Impairment (SNAKE)”. Children’s sleep behavior was increasingly conspicuous, with greater gross motor (SNAKE scales: disturbances remaining asleep, daytime sleepiness) and fine motor (additionally SNAKE scale arousal and breathing problems) functional impairment. Overall, a proportion of children showed sleep behavior outside the SNAKE’s normal range. No relevant sleep differences were identified between different CP subtypes and comorbidities. Applying a population-specific questionnaire, children’s functional impairment seems to be more relevant to their sleep behavior than the CP subtype or CP comorbidities.
Effect of Substrate Biasing on the Epitaxial Growth and Structural Properties of RF Magnetron Sputtered Germanium Buffer Layer on Silicon
Authors: Zeng Gui-Sheng , Liu Chi-Lung , Chen Sheng-Hui
Published: September 2021

High-quality single-crystal-like Ge (004) thin films have been epitaxially grown using radio-frequency magnetron sputtering on Si (001) substrates successfully. The crystalline quality of the Ge films can be obviously improved by applying a positive bias on the substrate holder. X-ray diffraction measurements show that the single-crystal-like Ge film has a narrow full width at half maximum of 0.26°. The perpendicular lattice constant (aGe⊥) and in-plane lattice constant (aGe∥) are 0.5671 and 0.564 nm. The Raman shift full width at half maximum shows that the defects in the film are obviously reduced. Transmission electron microscopy diffraction patterns also show that the Ge (004) film has good crystalline quality. The results can be applied as Ge buffer layers on Si substrates for the fabrication of high-efficiency III–V solar cells and photodetectors.
The Effect of High-Temperature Water Vapour on Degradation and Failure of Hot Section Components of Gas Turbine Engines
Authors: Chen Kuiying , Seo Dongyi , Canteenwalla Pervez
Published: September 2021

For the past decade, the aviation industry has been adopting sustainable aviation fuels (SAF) for use in aircraft to reduce the impact of aviation on climate change. Also, some nations look to SAF as an option for energy security for their military fleets. Understanding the critical impact of alternative fuel sources on hardware will provide the gas turbine industry with strategic options in sustainability and maintainability of the existing and new fleets. The alternative fuels with high hydrogen/carbon ratio (H/C) (such as synthetic paraffinic kerosenes (SPK)) could produce more water vapour content than the conventional jet fuels upon combustion, and this increased water vapour level could exert a significant impact over the long-term durability on hot section components such as the substrate blades, oxidation resistant coatings, thermal barrier coatings (TBCs), environmental barrier coatings (EBCs), resulting in an accelerated degradation of the turbine components. The possible detrimental effect of high-temperature water vapour on degradation and lifespan of hot section components was examined. Examples were specifically given on degradation and spallation of thermally grown oxides (TGO), formation of non-protective oxides and ceramics topcoats in TBCs. Results show that water vapour can lead to volatilization of TGO (Al2O3), and is responsible for the formation of non-protective oxides in both Pt-modified β-NiAl and MCrAlY coatings, leading to their early spallation. However, water vapour does not appear to directly affect the ceramic topcoat of the TBC. For EBCs coated on SiC-based substrates, the substrate recession via silica (TGO) volatilization was reviewed. These EBCs were observed undergoing degradation in highly hostile environments, e.g., constantly operating under high temperatures, pressures, and velocities condition in the presence of water vapour steam. The review intends to provide a perspective of high-temperature water vapour effect on the EBCs’ topcoat properties such as durability, degradation, crack nucleation and crack growth, and possible guidance for mitigating these degradation effects.
Microstructural Studies of the Copper-Based Coating Obtained by Cold Gas-Dynamic Spraying for the Restoration of Worn-Out Contact Wires
Authors: Grigoriev Sergey , Gershman Eugeniy , Gershman Iosif , Mironov Alexander , Podrabinnik Pavel
Published: September 2021

The microstructure of the coating obtained by cold gas-dynamic spraying was investigated. A Cu-Al2O3-Zn powder blend was sprayed onto a copper substrate to restore a worn copper contact wire. The coating thickness was 1–2.5 mm. Mechanisms of coating formation are discussed on the basis of microstructure studies. The relationship between the microstructure and the properties of the coating such as adhesion strength and electrical conductivity is shown. Improved adhesion strength was achieved through substrate surface preprocessing with coarse Al2O3 particles.
Superlow Friction of a-C:H Coatings in Vacuum: Passivation Regimes and Structural Characterization of the Sliding Interfaces
Authors: Kuwahara Takuya , Long Yun , De Barros Bouchet Maria-Isabel , Martin Jean Michel , Moras Gianpietro , Moseler Michael
Published: September 2021

A combination of atomistic simulations and vacuum tribometry allows atomic-scale insights into the chemical structure of superlubricious hydrogenated diamond-like carbon (a-C:H) interfaces in vacuum. Quantum molecular dynamics shearing simulations provide a structure-property map of the friction regimes that characterize the dry sliding of a-C:H. Shear stresses and structural properties at the sliding interfaces are crucially determined by the hydrogen content CH in the shear zone of the a-C:H coating. Extremely small CH (below 3 at.%) cause cold welding, mechanical mixing and high friction. At intermediate CH (ranging approximately from 3 to 20 at.%), cold welding in combination with mechanical mixing remains the dominant sliding mode, but some a-C:H samples undergo aromatization, resulting in a superlubricious sliding interface. A further increase in CH (above 20 at.%) prevents cold welding completely and changes the superlubricity mechanism from aromatic to hydrogen passivation. The hydrogen-passivated surfaces are composed of short hydrocarbon chains hinting at a tribo-induced oligomerization reaction. In the absence of cold welding, friction strongly correlates with nanoscale roughness, measured by the overlap of colliding protrusions at the sliding interface. Finally, the atomistic friction map is related to reciprocating friction experiments in ultrahigh vacuum. Accompanying X-ray photoelectron and Auger electron spectroscopy (XPS, XAES) analyses elucidate structural changes during vacuum sliding of a hydrogen-rich a-C:H with 36 at.% hydrogen. Initially, the a-C:H is covered by a nanometer-thick hydrogen-depleted surface layer. After a short running-in phase that results in hydrogen accumulation, superlubricity is established. XPS and XAES indicate a non-aromatic 1–2-nm-thick surface layer with polyethylene-like composition in agreement with our simulations.
Fracture Toughness Analysis of Aluminum (Al) Foil and Its Adhesion with Low-Density Polyethylene (LPDE) in the Packing Industry
Authors: Sharif Umer , Sun Beibei , Islam Md , Majeed Kashif , Ibrahim Dauda , Adewale Orelaja , Akhtar Naseem , Zaki Zaki , El-Bahy Zeinhom
Published: September 2021

Liquid food packages consist of various polymers films, which are bonded together with Aluminum foil (Al-foil) using adhesion or by direct heat. The main aim of this research was to define important material properties such as fracture toughness and some FE-simulation material model parameters such as damage initiation, damage evolution, and the adhesion between Al-foil and low-density polyethylene (LDPE) film. This investigation is based on both physical experiments and FE simulations in ABAQUS with and without initial cracks of different lengths for comparison purposes. The final FE model in ABAQUS was used to compare the numerical input parameters in an extensive study with the ambition to investigate the materials’ parameters in cases with or without adhesion between laminates. Finally, the relation between the theoretical and experimental results for Al-foil using linear elastic fracture mechanics and modified strip yield model were shown, and the fracture toughness was calculated for two different thicknesses of Al-foil.
Effect of Hydrated Deep Eutectic Solvents on the Thermal Stability of DNA
Authors: Tortora Mariagrazia , Vigna Jacopo , Mancini Ines , Mele Andrea , Gessini Alessandro , Masciovecchio Claudio , Rossi Barbara
Published: September 2021

DNA’s structure stability in hydrated deep eutectic solvents (DESs) is getting growing attention for emerging bio-applications. The employment of DESs as novel co-solvents in water media could favor eco-friendly and biodegradable materials for DNA storage and handling. Understanding the molecular interactions between nucleic acids and aqueous DES is crucial for developing new-generation solvents for biomolecules. In this work, we exploit the molecular sensitivity and selectivity of synchrotron radiation UV resonance raman (SR-UVRR) spectroscopy to explore the interplay between a choline chloride:urea (ChCl:U) DES and double-stranded DNA. Our study analyzes the impact of ChCl:U on the DNA’s thermal unfolding pathway by focusing on the guanine nucleobases whose Raman signal could be strongly enhanced through careful tuning of the excitation wavelength.
Magnetic Properties and Local Structure of the (La, Co) Co-doped Bi1−xLaxFe0.95Co0.05O3
Authors: Li Yongtao , Shi Chenyong , Zhang Hongguang , He Xuemin , Liu Liqing
Published: September 2021

In this study, the structural, morphological, and magnetic properties and the local structure of Bi1−xLaxFe0.95Co0.05O3 (x = 0.05, 0.10, 0.15, 0.20) nanoparticles were systematically investigated. In the (La, Co) co-doped BiFeO3 samples, a structural transition from a rhombohedral to orthorhombic structure was observed via X-ray diffraction. This structural phase transition resulted in significantly improved magnetic properties (Ms = 1.706 emu/g at 60 kOe). SEM analysis revealed that grain size decreased with increasing La concentration. The magnetic hysteresis loops confirmed that the significant enhancement of magnetization for all samples. Finally, combining the experimental synchrotron radiation techniques, we studied the samples’ local structure in order to analyze the reasons why the samples’ magnetic properties were enhanced.
Automatic Identification and Quantitative Characterization of Primary Dendrite Microstructure Based on Machine Learning
Authors: Wan Weihao , Li Dongling , Wang Haizhou , Zhao Lei , Shen Xuejing , Sun Dandan , Chen Jingyang , Xiao Chengbo
Published: September 2021

Dendrites are important microstructures in single-crystal superalloys. The distribution of dendrites is closely related to the heat treatment process and mechanical properties of single-crystal superalloys. The primary dendrite arm spacing (PDAS) is an important length scale to describe the distribution of dendrites. In this work, the second-generation single crystal superalloy HT901 with a diameter of 15 mm was imaged under a metallurgical microscope. An automatic dendrite core identification and full-field quantitative statistical analysis method is proposed to automatically detect the dendrite core and calculate the local PDAS. The Faster R-CNN algorithm combined with test time augmentation (TTA) technology is used to automatically identify the dendrite cores. The local multi-directional algorithm combined with Voronoi tessellation is used to determine the local nearest neighbor dendrite and calculate the local PDAS and coordination number. The accuracy of using Faster R-CNN combined with TTA to detect the dendrite core of HT901 reaches 98.4%, which is 15.9% higher than using Faster R-CNN alone. The algorithm calculates the local PDAS of all dendrites in H901 and captures the Gaussian distribution of the local PDAS. The average PDAS determined by the Gaussian distribution is 415 μm, which is only a small difference from the average spacing λ¯ (420 μm) calculated by the traditional method. The technology analyzes the relationship between the local PDAS and the distance from the center of the sample. The local PDAS near the center of HT901 are larger than those near the edge. The results suggests that the method enables the rapid, accurate and quantitative dendritic distribution characterization.
Microstructure and Elements Concentration of Inconel 713LC during Laser Powder Bed Fusion through a Modified Cellular Automaton Model
Authors: Ansari Dezfoli Amir Reza , Lo Yu-Lung , Raza M. Mohsin
Published: September 2021

In this study, a hybrid finite element (FE) and cellular automaton (CA) model is developed to explore crystallization behavior and alloying of Inconel713LC during Laser powder bed fusion. A cellular automaton model is considering the surface nucleation, equiaxed bulk nucleation, and grain growth kinetics. In addition, the equation for solute diffusion is coupled with a cellular automaton model to simulate the IN713LC elements segregation. During the phase change, the non-equilibrium segregation model is applied to insert the effect of ultra-fast solidification happening during LPBF. It is found that, during LPBF processing of IN713LC, the micro segregation of Nb, Ti, and C is accrued at the grain boundaries. It is further shown that the micro segregation intensity depends on the solidification speed, which is determined in turn by the laser heat input. In particular, a lower laser heat input increases the solidification speed and results in a more uniform solid phase, thereby reducing the risk of crack formation. Finally, using a comparison between simulation results and experimental observation, it was shown that the proposed model successfully predicts the bulk element concentration of IN713LC after laser melting.