bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of Naldemedine Compared with Magnesium Oxide in Preventing Opioid-Induced Constipation: A Randomized Controlled Trial
Authors: Ozaki Anna , Kessoku Takaomi , Tanaka Kosuke , Yamamoto Atsushi , Takahashi Kota , Takeda Yuma , Kasai Yuki , Iwaki Michihiro , Kobayashi Takashi , Yoshihara Tsutomu , Kato Takayuki , Suzuki Akihiro , Honda Yasushi , Ogawa Yuji , Fuyuki Akiko , Imajo Kento , Higurashi Takuma , Yoneda Masato , Taguri Masataka , Ishiki Hiroto , Kobayashi Noritoshi , Saito Satoru , Ichikawa Yasushi , Nakajima Atsushi
Published: April 2022

Opioid-induced constipation (OIC) may occur in patients receiving opioid treatment, decreasing their quality of life (QOL). We compared the effectiveness of magnesium oxide (MgO) with that of naldemedine (NAL) in preventing OIC. This proof-of-concept, randomized controlled trial (registration number UMIN000031891) involved 120 patients with cancer scheduled to receive opioid therapy. The patients were randomly assigned and stratified by age and sex to receive MgO (500 mg, thrice daily) or NAL (0.2 mg, once daily) for 12 weeks. The change in the average Japanese version of Patient Assessment of Constipation QOL (JPAC-QOL) from baseline to 2 weeks was assessed as the primary endpoint. The other endpoints were spontaneous bowel movements (SBMs) and complete SBMs (CSBMs). Deterioration in the mean JPAC-QOL was significantly lower in the NAL group than in the MgO group after 2 weeks. There were fewer adverse events in the NAL group than in the MgO group. Neither significant differences in the change in SBMs between the groups nor serious adverse events/deaths were observed. The CSBM rate was higher in the NAL group than in the MgO group at 2 and 12 weeks. In conclusion, NAL significantly prevented deterioration in constipation-specific QOL and CSBM rate compared with MgO.
Oral Etoposide and Trastuzumab Use for HER2-Positive Metastatic Breast Cancer: A Retrospective Study from the Institut Curie Hospitals
Authors: Chalumeau Clelia , Carton Matthieu , Eeckhoutte Alexandre , Ballet Stelly , Vincent-Salomon Anne , Vuagnat Perrine , Bellesoeur Audrey , Pierga Jean-Yves , Stern Marc-Henri , Bidard Francois-Clement , Lerebours Florence
Published: April 2022

Background: The TOP2A and ERBB2 genes are co-amplified in about 40% of HER2 positive (HER2+) breast cancers. Oral etoposide (VP16), an inhibitor of topoisomerase-II (encoded by TOP2A), has demonstrated clinical activity in metastatic breast cancer (MBC). The benefit of oral VP16 combined with trastuzumab (VP16-T) in HER2+ MBC has not yet been evaluated. Methods: Patients treated at the Institut Curie Hospitals with VP16-T for HER2+ MBC were retrieved by an in silico search. Progression-free survival (PFS), overall survival (OS), response rate, prolonged PFS (defined as at least 6 months), clinical benefit, and toxicity were assessed. The co-amplification of ERBB2 and TOP2A was assessed by shallow whole genome sequencing on tumor tissue whenever available. Results: Forty-three patients received VP16-T after a median number of six prior treatment lines for HER2+ MBC. Median PFS and OS were 2.9 months (95% CI [2.4–4.7]) and 11.3 months (95% CI [8.3–25.0]), respectively. Three patients had a complete response, while 12/40 (30%) experienced clinical benefit. Only three patients stopped treatment for toxicity. Seven (35%) patients displayed a TOP2A/ERBB2 co-amplification. No statistically significant correlation was found between outcome and TOP2A/ERBB2 co-amplification. Conclusion: Our analysis suggests a favorable efficacy and toxicity profile for VP16-T in patients with heavily pretreated HER2+ MBC.
Preoperative Management of Perihilar Cholangiocarcinoma
Authors: Ellis Ryan J. , Soares Kevin C. , Jarnagin William R.
Published: April 2022

Perihilar cholangiocarcinoma is a rare hepatobiliary malignancy that requires thoughtful, multidisciplinary evaluation in the preoperative setting to ensure optimal patient outcomes. Comprehensive preoperative imaging, including multiphase CT angiography and some form of cholangiographic assessment, is key to assessing resectability. While many staging systems exist, the Blumgart staging system provides the most useful combination of resectability assessment and prognostic information for use in the preoperative setting. Once resectability is confirmed, volumetric analysis should be performed. Upfront resection without biliary drainage or portal venous embolization may be considered in patients without cholangitis and an estimated functional liver remnant (FLR) > 40%. In patients with FLR < 40%, judicious use of biliary drainage is advised, with the goal of selective biliary drainage of the functional liver remnant. Percutaneous biliary drainage may avoid inadvertent contamination of the contralateral biliary tree and associated infectious complications, though the relative effectiveness of percutaneous and endoscopic techniques is an ongoing area of study and debate. Patients with low FLR also require intervention to induce hypertrophy, most commonly portal venous embolization, in an effort to reduce the rate of postoperative liver failure. Even with extensive preoperative workup, many patients will be found to have metastatic disease at exploration and diagnostic laparoscopy may reduce the rate of non-therapeutic laparotomy. Management of perihilar cholangiocarcinoma continues to evolve, with ongoing efforts to improve preoperative liver hypertrophy and to further define the role of transplantation in disease management.
Transition Metal Dichalcogenides [MX2] in Photocatalytic Water Splitting
Authors: Fadojutimi Paul O. , Gqoba Siziwe S. , Tetana Zikhona N. , Moma John
Published: April 2022

The quest for a clean, renewable and sustainable energy future has been highly sought for by the scientific community over the last four decades. Photocatalytic water splitting is a very promising technology to proffer a solution to present day environmental pollution and energy crises by generating hydrogen fuel through a “green route” without environmental pollution. Transition metal dichalcogenides (TMDCs) have outstanding properties which make them show great potential as effective co-catalysts with photocatalytic materials such as TiO2, ZnO and CdS for photocatalytic water splitting. Integration of TMDCs with a photocatalyst such as TiO2 provides novel nanohybrid composite materials with outstanding characteristics. In this review, we present the current state of research in the application of TMDCs in photocatalytic water splitting. Three main aspects which consider their properties, advances in the synthesis routes of layered TMDCs and their composites as well as their photocatalytic performances in the water splitting reaction are discussed. Finally, we raise some challenges and perspectives in their future application as materials for water-splitting photocatalysts.
Impact of Black Body Material Enhanced Gas Movement on CO2 Photocatalytic Reduction Performance
Authors: Nishimura Akira , Kato Takaharu , Mae Homare , Hu Eric
Published: April 2022

Gas movement around and/or through the photocatalyst is thought to be an inhibition factor to promote photocatalytic CO2 reduction performance. In this study, a hypothesis is put forward that the natural thermosiphon movement of gases around the photocatalyst can be improved by using black body material/surface. The black body material/surface that is placed underneath the photocatalyst in the reactor would be heated by absorbing light and then this heats up the gases to promote their movement around/through the photocatalyst. The aim of this study is to prove or disprove this hypothesis by conducting CO2 reduction performance of a TiO2 photocatalyst with NH3 under the conditions without black body material (W/O B.B.), with one black body material (W B.B.-1), and with three black body materials (W B.B.-3). The impact of molar ratio of CO2/NH3 on CO2 reduction performance is also investigated. This study revealed/proved that the hypothesis worked and that the CO2 reduction performance is promoted more with W B.B.-3 compared to that with W B.B.-1. The maximum concentration of formed CO with W B.B.-3 is two to five times as large as that under the condition W/O B.B.
Immobilization of Polyoxometalates on Carbon Nanotubes: Tuning Catalyst Activity, Selectivity and Stability in H2O2-Based Oxidations
Authors: Evtushok Vasilii Yu. , Lopatkin Vladimir A. , Podyacheva Olga Yu. , Kholdeeva Oxana A.
Published: April 2022

In recent years, carbon nanotubes (CNTs), including N-doped ones (N-CNTs), have received significant attention as supports for the construction of heterogeneous catalysts. In this work, we summarize our progress in the application of (N)-CNTs for immobilization of anionic metal-oxygen clusters or polyoxometalates (POMs) and use of (N)-CNTs-supported POM as catalysts for liquid-phase selective oxidation of organic compounds with the green oxidant–aqueous hydrogen peroxide. We discuss here the main factors, which favor adsorption of POMs on (N)-CNTs and ensure a quasi-molecular dispersion of POM on the surface and their strong attachment to the support. The effects of the POM nature, N-doping of CNTs, acid additives, and other factors on the POM immobilization process and catalytic activity/selectivity of the (N)-CNTs-immobilized POMs are analyzed. Particular attention is drawn to the critical issue of the catalyst stability and reusability. The scope and limitations of the POM/(N)-CNTs catalysts in H2O2-based selective oxidations are discussed.
PTCL1-EstA from Paenarthrobacter aurescens TC1, a Candidate for Industrial Application Belonging to the VIII Esterase Family
Authors: Li Qinyu , Chen Xiaojia , Liu Xiangcen , Chen Zheng , Han Yang , Zhou Peng , Shi Jiping , Zhao Zhijun
Published: April 2022

The esterase PTCL1-EstA from Paenarthrobacter aurescens TC1 was expressed in Escherichia coli and characterized. An 1152 bp open reading frame encoding a 383 amino acid polypeptide was successfully expressed, the C-terminally His6-tagged PTCL1-EstA enzyme was purified, and the predicted molecular mass of the purified PTCL1-EstA was 40.6 kDa. The EstA family serine hydrolase PTCL1-EstA belongs to the esterase family VIII, contains esterase-labeled S-C-S-K sequences, and homologous class C beta-lactamase sequences. PTCL1-EstA favored p-nitrophenyl esters with C2-C6 chain lengths, but it was also able to hydrolyze long-chain p-nitrophenyl esters. Homology modelling and substrate docking predicted that Ser59 was an active site residue in PTCL1-EstA, as well as Tyr148, Ala325, and Asp323, which are critical in catalyzing the enzymatic reaction of p-nitrophenyl esters. PTCL1-EstA reached the highest specific activity against p-nitrophenyl butyrate (C4) at pH 7.0 and 45 °C but revealed better thermal stability at 40 °C and maintained high relative enzymatic activity and stability at pH 5.0–9.0. Fermentation medium optimization for PTCL1-EstA increased the enzyme activity to 510.76 U/mL, tapping the potential of PTCL1-EstA for industrial production.
Chemo-Enzymatic Production of 4-Nitrophenyl-2-acetamido-2-deoxy-α-D-galactopyranoside Using Immobilized β-N-Acetylhexosaminidase
Authors: Hronská Helena , Štefuca Vladimír , Ondrejková Ema , Bláhová Mária , Višňovský Jozef , Rosenberg Michal
Published: April 2022

α-Nitrophenyl derivatives of glycosides are convenient substrates used to detect and characterize α-N-acetylgalactosaminidase. A new procedure combining chemical and biocatalytic steps was developed to prepare 4-nitrophenyl-2-acetamido-2-deoxy-α-D-galactopyranoside (4NP-α-GalNAc). The α-anomer was prepared through chemical synthesis of an anomeric mixture followed by selective removal of the β-anomer using specific enzymatic hydrolysis. Fungal β-N-acetylhexosaminidase (Hex) from Penicillium oxalicum CCF 1959 served this purpose owing to its high chemo-and regioselectivity towards the β-anomeric N-acetylgalactosamine (GalNAc) derivative. The kinetic measurements of the hydrolytic reaction showed that the enzyme was not inhibited by the substrate or reaction products. The immobilization of Hex in lens-shaped polyvinyl alcohol hydrogel capsules provided a biocatalyst with very good storage and operational stability. The immobilized Hex retained 97% of the initial activity after ten repeated uses and 90% of the initial activity after 18 months of storage at 4 °C. Immobilization inactivated 65% of the enzyme activity. However, the effectiveness factor and kinetic and mass transfer phenomena approached unity indicating negligible mass transfer limitations.
How to Make Sense out of 75,000 Mesenchymal Stromal Cell Publications?
Authors: Mönch Dina , Reinders Marlies E. J. , Dahlke Marc H. , Hoogduijn Martin J.
Published: April 2022

Mesenchymal stromal cells have been the subject of an expanding number of studies over the past decades. Today, over 75,000 publications are available that shine light on the biological properties and therapeutic effects of these versatile cells in numerous pre-clinical models and early-phase clinical trials. The massive number of papers makes it hard for researchers to comprehend the whole field, and furthermore, they give the impression that mesenchymal stromal cells are wonder cells that are curative for any condition. It is becoming increasingly difficult to dissect how and for what conditions mesenchymal stromal cells exhibit true and reproducible therapeutic effects. This article tries to address the question how to make sense of 75,000, and still counting, publications on mesenchymal stromal cells.
Proteostasis Perturbations and Their Roles in Causing Sterile Inflammation and Autoinflammatory Diseases
Authors: Papendorf Jonas Johannes , Krüger Elke , Ebstein Frédéric
Published: April 2022

Proteostasis, a portmanteau of the words protein and homeostasis, refers to the ability of eukaryotic cells to maintain a stable proteome by acting on protein synthesis, quality control and/or degradation. Over the last two decades, an increasing number of disorders caused by proteostasis perturbations have been identified. Depending on their molecular etiology, such diseases may be classified into ribosomopathies, proteinopathies and proteasomopathies. Strikingly, most—if not all—of these syndromes exhibit an autoinflammatory component, implying a direct cause-and-effect relationship between proteostasis disruption and the initiation of innate immune responses. In this review, we provide a comprehensive overview of the molecular pathogenesis of these disorders and summarize current knowledge of the various mechanisms by which impaired proteostasis promotes autoinflammation. We particularly focus our discussion on the notion of how cells sense and integrate proteostasis perturbations as danger signals in the context of autoinflammatory diseases to provide insights into the complex and multiple facets of sterile inflammation.
TRPM2 Promotes Atherosclerotic Progression in a Mouse Model of Atherosclerosis
Authors: Zhang Yunting , Ying Fan , Tian Xiaoyu , Lei Zhenchuan , Li Xiao , Lo Chun-Yin , Li Jingxuan , Jiang Liwen , Yao Xiaoqiang
Published: April 2022

Atherosclerosis is a chronic inflammatory arterial disease characterized by build-up of atheromatous plaque, which narrows the lumen of arteries. Hypercholesterolemia and excessive oxidative stress in arterial walls are among the main causative factors of atherosclerosis. Transient receptor potential channel M2 (TRPM2) is a Ca2+-permeable cation channel activated by oxidative stress. However, the role of TRPM2 in atherosclerosis in animal models is not well studied. In the present study, with the use of adeno-associated virus (AAV)-PCSK9 and TRPM2 knockout (TRPM2−/−) mice, we determined the role of TRPM2 in hypercholesterolemia-induced atherosclerosis. Our results demonstrated that TRPM2 knockout reduced atherosclerotic plaque area in analysis of En face Oil Red O staining of both whole aortas and aortic-root thin sections. Furthermore, TRPM2 knockout reduced the expression of CD68, α-SMA, and PCNA in the plaque region, suggesting a role of TRPM2 in promoting macrophage infiltration and smooth-muscle cell migration into the lesion area. Moreover, TRPM2 knockout reduced the expression of ICAM-1, MCP-1, and TNFα and decreased the ROS level in the plaque region, suggesting a role of TRPM2 in enhancing monocyte adhesion and promoting vascular inflammation. In bone-marrow-derived macrophages and primary cultured arterial endothelial cells, TRPM2 knockout reduced the production of inflammatory cytokines/factors and decreased ROS production. In addition, a TRPM2 antagonist N-(p-amylcinnamoyl) anthranilic acid (ACA) was able to inhibit atherosclerotic development in an ApoE−/− mouse model of atherosclerosis. Taken together, the findings of our study demonstrated that TRPM2 contributes to the progression of hypercholesterolemia-induced atherosclerosis. Mechanistically, TRPM2 channels may provide an essential link that can connect ROS to Ca2+ and inflammation, consequently promoting atherosclerotic progression.
New Insights into Adipose Tissue Macrophages in Obesity and Insulin Resistance
Authors: Cai Zhaohua , Huang Yijie , He Ben
Published: April 2022

Obesity has become a worldwide epidemic that poses a severe threat to human health. Evidence suggests that many obesity comorbidities, such as type 2 diabetes mellitus, steatohepatitis, and cardiovascular diseases, are related to obesity-induced chronic low-grade inflammation. Macrophages are the primary immune cells involved in obesity-associated inflammation in both mice and humans. Intensive research over the past few years has yielded tremendous progress in our understanding of the additional roles of adipose tissue macrophages (ATMs) beyond classical M1/M2 polarization in obesity and related comorbidities. In this review, we first characterize the diverse subpopulations of ATMs in the context of obesity. Furthermore, we review the recent advance on the role of the extensive crosstalk between adipocytes and ATMs in obesity. Finally, we focus on the extended crosstalk within adipose tissue between perivascular mesenchymal cells and ATMs. Understanding the pathological mechanisms that underlie obesity will be critical for the development of new intervention strategies to prevent or treat this disease and its associated co-morbidities.
Rabeprazole Promotes Vascular Repair and Resolution of Sepsis-Induced Inflammatory Lung Injury through HIF-1α
Authors: Evans Colin E. , Peng Yi , Zhu Maggie M. , Dai Zhiyu , Zhang Xianming , Zhao You-Yang
Published: April 2022

There are currently no effective treatments for sepsis and acute respiratory distress syndrome (ARDS). The repositioning of existing drugs is one possible effective strategy for the treatment of sepsis and ARDS. We previously showed that vascular repair and the resolution of sepsis-induced inflammatory lung injury is dependent upon endothelial HIF-1α/FoxM1 signaling. The aim of this study was to identify a candidate inducer of HIF-1α/FoxM1 signaling for the treatment of sepsis and ARDS. Employing high throughput screening of a library of 1200 FDA-approved drugs by using hypoxia response element (HRE)-driven luciferase reporter assays, we identified Rabeprazole (also known as Aciphex) as a top HIF-α activator. In cultured human lung microvascular endothelial cells, Rabeprazole induced HIF1A mRNA expression in a dose-dependent manner. A dose-response study of Rabeprazole in a mouse model of endotoxemia-induced inflammatory lung injury identified a dose that was well tolerated and enhanced vascular repair and the resolution of inflammatory lung injury. Rabeprazole treatment resulted in reductions in lung vascular leakage, edema, and neutrophil sequestration and proinflammatory cytokine expression during the repair phrase. We next used Hif1a/Tie2Cre knockout mice and Foxm1/Tie2Cre knockout mice to show that Rabeprazole promoted vascular repair through HIF-1α/FoxM1 signaling. In conclusion, Rabeprazole is a potent inducer of HIF-1α that promotes vascular repair and the resolution of sepsis-induced inflammatory lung injury via endothelial HIF-1α/FoxM1 signaling. This drug therefore represents a promising candidate for repurposing to effectively treat severe sepsis and ARDS.
Pls1 Is a Peroxisomal Matrix Protein with a Role in Regulating Lysine Biosynthesis
Authors: David Yotam , Castro Inês Gomes , Yifrach Eden , Bibi Chen , Katawi Enas , Yahav Har-Shai Dekel , Brodsky Sagie , Barkai Naama , Ravid Tommer , Eisenstein Miriam , Pietrokovski Shmuel , Schuldiner Maya , Zalckvar Einat
Published: April 2022

Peroxisomes host essential metabolic enzymes and are crucial for human health and survival. Although peroxisomes were first described over 60 years ago, their entire proteome has not yet been identified. As a basis for understanding the variety of peroxisomal functions, we used a high-throughput screen to discover peroxisomal proteins in yeast. To visualize low abundance proteins, we utilized a collection of strains containing a peroxisomal marker in which each protein is expressed from the constitutive and strong TEF2 promoter. Using this approach, we uncovered 18 proteins that were not observed in peroxisomes before and could show their metabolic and targeting factor dependence for peroxisomal localization. We focus on one newly identified and uncharacterized matrix protein, Ynl097c-b, and show that it localizes to peroxisomes upon lysine deprivation and that its localization to peroxisomes depends on the lysine biosynthesis enzyme, Lys1. We demonstrate that Ynl097c-b affects the abundance of Lys1 and the lysine biosynthesis pathway. We have therefore renamed this protein Pls1 for Peroxisomal Lys1 Stabilizing 1. Our work uncovers an additional layer of regulation on the central lysine biosynthesis pathway. More generally it highlights how the discovery of peroxisomal proteins can expand our understanding of cellular metabolism.
Prognostic and Immunotherapeutic Roles of KRAS in Pan-Cancer
Authors: Yang Kaixin , Li Chengyun , Liu Yang , Gu Xueyan , Jiang Longchang , Shi Lei
Published: April 2022

KRAS is one well-established tumor-driver gene associated with cancer initiation, development, and progression. Nonetheless, comparative studies of the relevance of KRAS across diverse tumors remain sparse. We explored the KRAS expression and prognostic values in diverse cancer types via multiple web-based bioinformatics tools, including cBioPortal, Oncomine, PrognoScan, Kaplan–Meier Plotter, etc. We found that KRAS is highly expressed in various malignancies compared to normal cohorts (BRCA, CHOL, ESCA, HNSC, LIHC, LUAD, LUSC, and STAD) and less expressed in COAD, KIRC, READ, and THCA than in normal samples. We observed the dysregulation of the DNA methylation of KRAS in cancers and discovered that numerous oncogenic and tumor-suppressive transcription factors bind the KRAS promoter region. Pan-cancer analysis also showed that a high level of KRAS is associated with poor outcomes. Additionally, KRAS is remarkably correlated with the level of immune cell infiltration and tumorigenic gene signatures. In conclusion, our findings reveal novel insights into KRAS expression and its biological functions in diverse cancer types, indicating that KRAS could serve as a prognostic biomarker and is associated with immune infiltrates.
High-Throughput Analysis of Astrocyte Cultures Shows Prevention of Reactive Astrogliosis by the Multi-Nutrient Combination Fortasyn Connect
Authors: Badia-Soteras Aina , de Vries Janneke , Dykstra Werner , Broersen Laus M. , Verkuyl Jan Martin , Smit August B. , Verheijen Mark H. G.
Published: April 2022

Astrocytes are specialized glial cells that tile the central nervous system (CNS) and perform numerous essential functions. Astrocytes react to various forms of CNS insults by altering their morphology and molecular profile, through a process known as reactive astrogliosis. Accordingly, astrocyte reactivity is apparent in many neurodegenerative diseases, among which one is Alzheimer’s disease (AD). Recent clinical trials on early-stage AD have demonstrated that Fortasyn Connect (FC), a multi-nutrient combination providing specific precursors and cofactors for phospholipid synthesis, helps to maintain neuronal functional connectivity and cognitive performance of patients. Several studies have shown that FC may act through its effects on neuronal survival and synaptogenesis, leading to reduced astrocyte reactivity, but whether FC can directly counteract astrocyte reactivity remains to be elucidated. Hence, we developed an in vitro model of reactive astrogliosis using the pro-inflammatory cytokines TNF-α and IFN-γ together with an automated high-throughput assay (AstroScan) to quantify molecular and morphological changes that accompany reactive astrogliosis. Next, we showed that FC is potent in preventing cytokine-induced reactive astrogliosis, a finding that might be of high relevance to understand the beneficial effects of FC-based interventions in the context of neurodegenerative diseases.
Astrocytes Derived from Familial and Sporadic Alzheimer’s Disease iPSCs Show Altered Calcium Signaling and Respond Differently to Misfolded Protein Tau
Authors: Brezovakova Veronika , Sykova Eva , Jadhav Santosh
Published: April 2022

Astrocytes regulate important functions in the brain, and their dysregulation has been linked to the etiology of neurodegenerative diseases, such as Alzheimer’s disease (AD). The role of astroglia in human AD remains enigmatic, owing to the limitations of animal models, which, while recreating some pathological aspects of the disease, do not fully mirror its course. In addition, the recognition of major structural and functional differences between human and mouse astrocytes has also prompted research into human glial cells. In the current study, astrocytes were generated using human iPSCs from patients with sporadic Alzheimer’s disease (sAD), familial Alzheimer’s disease (fAD) and non-demented controls (NDC). All clones gained astrocyte-specific morphological and proteomic characteristics upon in vitro differentiation, without considerable inter-clonal variances. In comparison to NDC, AD astrocytes displayed aberrant calcium dynamics in response to glutamate. When exposed to monomeric and aggregated tau, AD astrocytes demonstrated hypertrophy and elevated GFAP expression, differential expression of select signaling and receptor proteins, and the enhanced production of metalloproteinases (MMPs). Moreover, astrocytic secretomes were able to degrade tau in both monomeric and pathologically aggregated forms, which was mediated by MMP-2 and -9. The capacity to neutralize tau varied considerably between clones, with fAD astrocytes having the lowest degradability relative to sAD and healthy astrocytes. Importantly, when compared to aggregated tau alone, astrocytic secretome pretreatment of tau differentially reduced its detrimental effects on neurons. Our results show crucial differences in sporadic and familial AD astrocytes and suggests that these cells may play distinctive roles in the pathogenesis of early and late onset Alzheimer’s disease.
SARS-CoV-2 Infection of Human Ovarian Cells: A Potential Negative Impact on Female Fertility
Authors: Luongo Francesca P. , Dragoni Filippo , Boccuto Adele , Paccagnini Eugenio , Gentile Mariangela , Canosi Tamara , Morgante Giuseppe , Luddi Alice , Zazzi Maurizio , Vicenti Ilaria , Piomboni Paola
Published: April 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may affect female reproductive health. Here, we investigated the potential of SARS-CoV-2 to infect the follicular microenvironment, in particular granulosa (GCs) and cumulus cells (CCs), thus providing evidence for a productive infection. GCs and CCs were recovered from women (n = 25) who underwent in vitro fertilization at the Assisted Reproductive Unit, Siena University Hospital. Follicular ovarian cells were co-cultured with SARS-CoV-2 and then analyzed by qPCR, immunofluorescence (IF), western blot (WB) and transmission electron microscopy (TEM). In addition, cell culture supernatant was used to infect VERO6 cells. We demonstrated the expression of cell host factors ACE2, TRPMSS2, BSG and CTSL, which are pivotal for the virus life cycle. Cultured GCs and CCs incubated with SARS-CoV-2 revealed productive SARS-CoV-2 infection at 24 h, 48 h and 72 h post-adsorption. Indeed, SARS-CoV-2 RNA, spike and nucleocapsid proteins were detected in GCs and CCs, and their cell culture supernatant successfully infected the standard VERO E6 cells. Finally, TEM showed full-size virions attached to the membrane and located inside the cytoplasm. This in vitro study reveals the susceptibility of human ovarian cells to SARS-CoV-2 infection, suggesting a potential detrimental effect of COVID-19 infection on female human fertility.
The Role of Extracellular Vesicles in Metabolic Reprogramming of the Tumor Microenvironment
Authors: Fridman Eran S. , Ginini Lana , Gil Ziv
Published: April 2022

The tumor microenvironment (TME) includes a network of cancerous and non-cancerous cells, together with associated blood vessels, the extracellular matrix, and signaling molecules. The TME contributes to cancer progression during various phases of tumorigenesis, and interactions that take place within the TME have become targets of focus in cancer therapy development. Extracellular vesicles (EVs) are known to be conveyors of genetic material, proteins, and lipids within the TME. One of the hallmarks of cancer is its ability to reprogram metabolism to sustain cell growth and proliferation in a stringent environment. In this review, we provide an overview of TME EV involvement in the metabolic reprogramming of cancer and stromal cells, which favors cancer progression by enhancing angiogenesis, proliferation, metastasis, treatment resistance, and immunoevasion. Targeting the communication mechanisms and systems utilized by TME-EVs is opening a new frontier in cancer therapy.
cGAS Regulates the Radioresistance of Human Head and Neck Squamous Cell Carcinoma Cells
Authors: Nyui Taichi , Yoshino Hironori , Nunota Tetsuya , Sato Yoshiaki , Tsuruga Eichi
Published: April 2022

Cyclic GMP-AMP synthase (cGAS) plays an important role in biological responses to pathogens. The activation of the cGAS pathway in immune cells is known to induce antitumor effects, but the role of cGAS in cancer cells remains poorly understood. In silico analysis using public databases suggested that high cGAS expression in head and neck squamous cell carcinoma (HNSCC) is indicative of a poor prognosis for HNSCC patients. We therefore investigated the role of cGAS in malignancies and the cellular radiation response of human HNSCC cells (SAS and Ca9-22) in vitro, because radiotherapy is one of the treatments most commonly used for HNSCC. Although cGAS knockdown failed to suppress the proliferation of non-irradiated HNSCC cells, it enhanced the radiosensitivity of HNSCC cells. The administration of the cGAS agonist increased the radioresistance of HNSCC cells. cGAS knockdown increased radiation-induced mitotic catastrophe, apoptosis, or cellular senescence, depending on the cell line, and this cell line-dependent response might be due to different responses of p21 after irradiation. Collectively, our findings indicate that the cGAS pathway regulates the radioresistance of HNSCC cells.
The Phenotype of the Adipocytes Derived from Subcutaneous and Visceral ADMSCs Is Altered When They Originate from Morbidly Obese Women: Is There a Memory Effect?
Authors: Mikłosz Agnieszka , Łukaszuk Bartłomiej , Supruniuk Elżbieta , Grubczak Kamil , Starosz Aleksandra , Kusaczuk Magdalena , Naumowicz Monika , Chabowski Adrian
Published: April 2022

Adipose tissue is an abundant source of mesenchymal stem cells (ADMSCs). Evidence has suggested that depot-specific ADMSCs (obtained from subcutaneous or visceral adipose tissue–subADMSCs or visADMSCs, respectively) account for differential responses of each depot to metabolic challenges. However, little is known about the phenotype and changes in metabolism of the adipocytes derived from ADMSCs of obese individuals. Therefore, we investigated the phenotypic and metabolic characteristics, particularly the lipid profile, of fully differentiated adipocytes derived from ADMSCs of lean and obese (with/without metabolic syndrome) postmenopausal women. We observed a depot-specific pattern, with more pronounced changes present in the adipocytes obtained from subADMSCs. Namely, chronic oversupply of fatty acids (present in morbid obesity) triggered an increase in CD36/SR-B2 and FATP4 protein content (total and cell surface), which translated to an increased LCFA influx (3H-palmitate uptake). This was associated with the accumulation of TAG and DAG in these cells. Furthermore, we observed that the adipocytes of visADMSCs origin were larger and showed smaller granularity than their counterparts of subADMSCs descent. Although ADMSCs were cultured in vitro, in a fatty acids-deprived environment, obesity significantly influenced the functionality of the progenitor adipocytes, suggesting the existence of a memory effect.
Obesity Affects the Proliferative Potential of Equine Endometrial Progenitor Cells and Modulates Their Molecular Phenotype Associated with Mitochondrial Metabolism
Authors: Smieszek Agnieszka , Marcinkowska Klaudia , Pielok Ariadna , Sikora Mateusz , Valihrach Lukas , Carnevale Elaine , Marycz Krzysztof
Published: April 2022

The study aimed to investigate the influence of obesity on cellular features of equine endometrial progenitor cells (Eca EPCs), including viability, proliferation capacity, mitochondrial metabolism, and oxidative homeostasis. Eca EPCs derived from non-obese (non-OB) and obese (OB) mares were characterized by cellular phenotype and multipotency. Obesity-induced changes in the activity of Eca EPCs include the decline of their proliferative activity, clonogenic potential, mitochondrial metabolism, and enhanced oxidative stress. Eca EPCs isolated from obese mares were characterized by an increased occurrence of early apoptosis, loss of mitochondrial dynamics, and senescence-associated phenotype. Attenuated metabolism of Eca EPCs OB was related to increased expression of pro-apoptotic markers (CASP9, BAX, P53, P21), enhanced expression of OPN, PI3K, and AKT, simultaneously with decreased signaling stabilizing cellular homeostasis (including mitofusin, SIRT1, FOXP3). Obesity alters functional features and the self-renewal potential of endometrial progenitor cells. The impaired cytophysiology of progenitor cells from obese endometrium predicts lower regenerative capacity if used as autologous transplants.
Fas/CD95 Signaling Pathway in Damage-Associated Molecular Pattern (DAMP)-Sensing Receptors
Authors: Galli Gael , Vacher Pierre , Ryffel Bernhard , Blanco Patrick , Legembre Patrick
Published: April 2022

Study of the initial steps of the CD95-mediated signaling pathways is a field of intense research and a long list of actors has been described in the literature. Nonetheless, the dynamism of protein-protein interactions (PPIs) occurring in the presence or absence of its natural ligand, CD95L, and the cellular distribution where these PPIs take place render it difficult to predict what will be the cellular outcome associated with the receptor engagement. Accordingly, CD95 stimulation can trigger apoptosis, necroptosis, pyroptosis, or pro-inflammatory signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and phosphatidylinositol-3-kinase (PI3K). Recent data suggest that CD95 can also activate pattern recognition receptors (PRRs) known to sense damage-associated molecular patterns (DAMPs) such as DNA debris and dead cells. This activation might contribute to the pro-inflammatory role of CD95 and favor cancer development or severity of chronic inflammatory and auto-immune disorders. Herein, we discuss some of the molecular links that might connect the CD95 signaling to DAMP sensors.
Bronchoalveolar-Lavage-Derived Fibroblast Cell Line (B-LSDM7) as a New Protocol for Investigating the Mechanisms of Idiopathic Pulmonary Fibrosis
Authors: Bergantini Laura , d’Alessandro Miriana , Gangi Sara , Cavallaro Dalila , Campiani Giuseppe , Butini Stefania , Landi Claudia , Bini Luca , Cameli Paolo , Bargagli Elena
Published: April 2022

Background: The use of BAL to study ILDs has improved our understanding of IPF pathogenesis. BAL fluid is routinely collected and can be considered a clinical and research tool. The procedure is well tolerated and minimally invasive. No specific cell lines from BAL or immortalized cell lines from IPF patients are available commercially. A method to quickly isolate and characterize fibroblasts from BAL is an unmet research need. Materials and methods: Here we describe a new protocol by which we isolated a cell line from IPF. The cell line was expanded in vitro and characterized phenotypically, morphologically and functionally. Results: This culture showed highly filamentous cells with an evident central nucleus. From the phenotypic point of view, this cell line displays fibroblast/myofibroblast-like features including expression of alpha-SMA, vimentin, collagen type-1 and fibronectin. The results showed high expression of ROS in these cells. Oxidative stress invariably promotes extracellular matrix expression in lung diseases directly or through over-production of pro-fibrotic growth factors. Conclusions: Our protocol makes it possible to obtain fibroblasts BAL that is a routine non-invasive method that offers the possibility of having a large sample of patients. Standardized culture methods are important for a reliable model for testing molecules and eventual novel development therapeutic targets.
Pathophysiology, Management and Quality of Life in Atopic Dermatitis and Psoriasis—A Challenge for Patients and Their Families
Authors: Callea Michele
Published: April 2022

In this Special Issue of Children, we present two articles: one detailing the pathophysiology of atopic dermatitis (AD) and psoriasis and highlighting recommendationsin regard to the implications for management in children [...]
Gait Adaptation Is Different between the Affected and Unaffected Legs in Children with Spastic Hemiplegic Cerebral Palsy While Walking on a Changing Slope
Authors: Choi Tae Young , Park Dongho , Shim Dain , Choi Joong-on , Hong Juntaek , Ahn Yongjin , Park Eun Sook , Rha Dong-wook
Published: April 2022

Walking on sloped surfaces requires additional effort; how individuals with spastic hemiplegic cerebral palsy (CP) manage their gait on slopes remains unknown. Herein, we analyzed the difference in gait adaptation between the affected and unaffected legs according to changes in the incline by measuring spatiotemporal and kinematic data in children with spastic hemiplegic CP. Seventeen children underwent instrumented three-dimensional gait analysis on a dynamic pitch treadmill at an incline of +10° to −10° (intervals of 5°). While the step length of the affected legs increased during uphill gait and decreased during downhill gait, the unaffected legs showed no significance. During uphill gait, the hip, knee, and ankle joints of the affected and unaffected legs showed increased flexion, while the unaffected leg showed increased knee flexion throughout most of the stance phase compared with the affected leg. During downhill gait, hip and knee flexion increased in the affected leg, and knee flexion increased in the unaffected leg during the early swing phase. However, the ankle plantar flexion increased during the stance phase only in the unaffected leg. Although alterations in temporospatial variables and joint kinematics occurred in both legs as the slope angle changed, they showed different adaptation mechanisms.
Recovery of the Foot Loading Patterns of Children with Excess Weight after Losing Weight: A 3-Year Longitudinal Study
Authors: Li Ruoyi , Sun Xiaohong , Yan Shiyang , Zhao Yihong , Badurova Jitka , Yang Luming , Fan Haojun
Published: April 2022

It is suggested that children with excess weight should lose weight to reduce plantar pressure and the risk of related injuries. However, whether the foot loading patterns of these children could return to normal after weight loss is unclear. A total of 147 children participated in this longitudinal study; 51 were selected for analysis—13 children who were overweight and 1 child with obesity reduced their weight to normal levels and 37 children maintained normal weights (control group). The plantar pressure parameters, including peak pressure, maximum force, and force-time integral were recorded using a Footscan plate system. Comparisons of plantar parameters and load transferences revealed that weight loss could effectively decrease the differences in foot loading distributions between the weight-reduced and normal-weight groups. After losing weight, the foot loading patterns of the children who were overweight recovered to the level of normal-weight children, and that of the child with obesity failed to reach the normal level. Losing weight is suggested for children who are overweight/obese to recover their foot loading patterns, to avoid further adverse influences on the foot/functioning caused by excessive weight-bearing. Further research exploring the findings of a cohort of children with obesity—who reduce their weight to normal levels—is warranted.
Technology in Rehabilitative Interventions for Children: Challenges and Opportunities
Authors: Traficante Daniela , Antonietti Alessandro
Published: April 2022

Technology innovation has been leading to the development of an increasing number of applications that aim to support the rehabilitation of cognitive functions [...]
Modeling of Progressive Scouring of a Pier-on-Bank
Authors: Chavan Vidya Subhash , Chen Shen-En , Shanmugam Navanit Sri , Tang Wenwu , Diemer John , Allan Craig , Braxtan Nicole , Shukla Tarini , Chen Tianyang , Slocum Zachery
Published: April 2022

Scour, caused by swiftly moving water, can remove alluvial sediment and soil, creating holes surrounding a bridge component and compromising the integrity of the bridge structure. Such problems can be equally critical for bridges with piers-on-bank bridges subjected to severe storm and flooding issues. In this paper, the Phillips Road Bridge over Toby Creek (35°18′28.2″ N 80°44′16.6″ W, Charlotte, NC, USA), a pier-on-bank bridge with critical/significant local scour holes and deep riverbank erosion cuts was selected as case study bridge. To investigate the scour effect on the bridge with pier-on-bank performance, the scoured area around a single pier is first quantified using a terrestrial laser and then modeled using nonlinear finite element (FE) analysis, where the local scour is modeled as progressive mass losses using the Element Removal (ER) technique. The FE results are compared to the design loading scenario and the results substantiated that the local scouring could cause large deflection and increased bending moment on the bridge pier.
Structural and Chemical Peculiarities of Nitrogen-Doped Graphene Grown Using Direct Microwave Plasma-Enhanced Chemical Vapor Deposition
Authors: Meškinis Šarūnas , Gudaitis Rimantas , Andrulevičius Mindaugas , Lazauskas Algirdas
Published: April 2022

Chemical vapor deposition (CVD) is an attractive technique which allows graphene with simultaneous heteroatom doping to be synthesized. In most cases, graphene is grown on a catalyst, followed by the subsequent transfer process. The latter is responsible for the degradation of the carrier mobility and conductivity of graphene due to the presence of the absorbants and transfer-related defects. Here, we report the catalyst-less and transfer-less synthesis of graphene with simultaneous nitrogen doping in a single step at a reduced temperature (700 °C) via the use of direct microwave plasma-enhanced CVD. By varying nitrogen flow rate, we explored the resultant structural and chemical properties of nitrogen-doped graphene. Atomic force microscopy revealed a more distorted growth process of graphene structure with the introduction of nitrogen gas—the root mean square roughness increased from 0.49 ± 0.2 nm to 2.32 ± 0.2 nm. Raman spectroscopy indicated that nitrogen-doped, multilayer graphene structures were produced using this method. X-ray photoelectron spectroscopy showed the incorporation of pure pyridinic N dopants into the graphene structure with a nitrogen concentration up to 2.08 at.%.
Carbon-Supported Noble-Metal Nanoparticles for Catalytic Applications—A Review
Authors: Karczmarska Agnieszka , Adamek Michał , El Houbbadi Sara , Kowalczyk Paweł , Laskowska Magdalena
Published: April 2022

Noble-metal nanoparticles (NMNPs), with their outstanding properties, have been arousing the interest of scientists for centuries. Although our knowledge of them is much more significant today, and we can obtain NMNPs in various sizes, shapes, and compositions, our interest in them has not waned. When talking about noble metals, gold, silver, and platinum come to mind first. Still, we cannot forget about elements belonging to the so-called platinum group, such as ruthenium, rhodium, palladium, osmium, and iridium, whose physical and chemical properties are very similar to those of platinum. It makes them highly demanded and widely used in various applications. This review presents current knowledge on the preparation of all noble metals in the form of nanoparticles and their assembling with carbon supports. We focused on the catalytic applications of these materials in the fuel-cell field. Furthermore, the influence of supporting materials on the electrocatalytic activity, stability, and selectivity of noble-metal-based catalysts is discussed.
Effect of Arc Behaviour and Metal Transfer Process on Aluminium Welds during Ultrasonic Frequency Pulsed GMAW
Authors: Zheng Hao , Qi Bojin , Yang Mingxuan , Liu Heng
Published: April 2022

In order to study the influence of a novel current waveform control method of ultrasonic-frequency pulse (UFP) on arc behaviour, metal transfer process and the welds formation, monitoring system and image processing algorithms were employed for extracting the welding characters. Mechanics, defect, microstructure and mechanical property analysis based on pulsed GMAW was carried out. The results showed that, compared with the conventional pulsed GMAW, the ultrasonic-frequency pulse not only increased axial arc plasma jet force, arc force and droplet falling acceleration, but also suppressed the welded porosity formation, decelerated the microstructure regional element segregations, refined the grain and increased the microhardness property of welded joint. The study helped to reveal the mechanism for improving welding quality of ultrasonic-frequency pulsed GMAW.
Effect of Hydrogen Migration in SiO2/Al2O3 Stacked Gate Insulator of InGaZnO Thin-Film Transistors
Authors: Park Shinyoung , Youn Sangwook , Jang Jun Tae , Kim Hyungjin , Kim Dae Hwan
Published: April 2022

In this work, the correlation between SiO2 deposition thickness and hydrogen content is discussed and the effect of the SiO2 layer on the properties of synaptic InGaZnO (IGZO) TFTs is analyzed. Three types of IGZO synaptic thin-film transistors (TFTs) were fabricated with different gate insulators, and the effect of SiO2 as a gate insulator was investigated. XPS analysis confirmed that the hydrogen content in the Al2O3 and SiO2 layers increased during SiO2 deposition step for all depth regions. Hydrogen injected by the SiO2 layer deposition step was confirmed to improve the memory window through more threshold voltage shift under positive bias stress (PBS) and negative bias stress (NBS) conditions. In addition, the retention characteristics were improved due to the low hydrogen movement velocity in the SiO2 layer. These results contribute to the optimization of the amount of hydrogen, and the proposed device has potential as a synaptic device capable of neuromorphic computing.