bluuebunny/crossref_metadata_2025 huggingface dataset:
Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers
Authors: Kapur Arvinder , Mehta Pooja , Simmons Aaron D , Ericksen Spencer S. , Mehta Geeta , Palecek Sean P. , Felder Mildred , Stenerson Zach , Nayak Amruta , Dominguez Jose Maria Ayuso , Patankar Manish , Barroilhet Lisa M.
Published: May 2022

Oxidative phosphorylation is an active metabolic pathway in cancer. Atovaquone is an oral medication that inhibits oxidative phosphorylation and is FDA-approved for the treatment of malaria. We investigated its potential anti-cancer properties by measuring cell proliferation in 2D culture. The clinical formulation of atovaquone, Mepron, was given to mice with ovarian cancers to monitor its effects on tumor and ascites. Patient-derived cancer stem-like cells and spheroids implanted in NSG mice were treated with atovaquone. Atovaquone inhibited the proliferation of cancer cells and ovarian cancer growth in vitro and in vivo. The effect of atovaquone on oxygen radicals was determined using flow and imaging cytometry. The oxygen consumption rate (OCR) in adherent cells was measured using a Seahorse XFe96 Extracellular Flux Analyzer. Oxygen consumption and ATP production were inhibited by atovaquone. Imaging cytometry indicated that the majority of the oxygen radical flux triggered by atovaquone occurred in the mitochondria. Atovaquone decreased the viability of patient-derived cancer stem-like cells and spheroids implanted in NSG mice. NMR metabolomics showed shifts in glycolysis, citric acid cycle, electron transport chain, phosphotransfer, and metabolism following atovaquone treatment. Our studies provide the mechanistic understanding and preclinical data to support the further investigation of atovaquone’s potential as a gynecologic cancer therapeutic.
Shifting the Soil: Metformin Treatment Decreases the Protumorigenic Tumor Microenvironment in Epithelial Ovarian Cancer
Authors: Taylor Sarah E. , Chan Daniel K. , Yang Dongli , Bruno Tulia , Lieberman Richard , Siddiqui Javed , Soong Thing Rinda , Coffman Lan , Buckanovich Ronald J.
Published: May 2022

Controversy persists regarding metformin’s role in cancer therapy. Our recent work suggested metformin acts by impacting the tumor microenvironment (TME), normalizing the epigenetic profile of cancer-associated mesenchymal stem cells (CA-MSC). As CA-MSC can negatively impact tumor immune infiltrates, we evaluated metformin’s impact on the human TME, focusing on the interplay of stroma and immune infiltrates. Tumor samples from (i) 38 patients treated with metformin and chemotherapy and (ii) 44 non-metformin matched controls were included in a tissue microarray (TMA). The TMA was used to compare the presence of CA-MSC, desmoplasia and immune infiltrates in the TME. In vitro and in vivo models examined metformin’s role in alteration of the CA-MSC phenotype. The average percentage of CA-MSC was significantly lower in metformin-treated than in chemotherapy alone-treated tumors (p = 0.006). There were fewer regulatory T-cells in metformin-treated tumors (p = 0.043). Consistent with CA-MSC’s role in excluding T-cells from tumor islets, the T-cells were primarily present within the tumor stroma. Evaluation of metformin’s impact in vitro suggested that metformin cannot reverse a CA-MSC phenotype; however, the in vivo model where metformin was introduced prior to the establishment of the CA-MSC phenotype supported that metformin can partially prevent the reprogramming of normal MSC into CA-MSC. Metformin treatment led to a decrease in both the presence of protumorigenic CA-MSC and in immune exclusion of T cells, leading to a more immune-permissive environment. This suggests clinical utility in prevention and in treatment for early-stage disease and putatively in immune therapy.
CD117, BAP1, MTAP, and TdT Is a Useful Immunohistochemical Panel to Distinguish Thymoma from Thymic Carcinoma
Authors: Angirekula Mounika , Chang Sindy Y , Jenkins Sarah M. , Greipp Patricia T. , Sukov William R. , Marks Randolph S. , Olivier Kenneth R. , Cassivi Stephen D. , Roden Anja C
Published: May 2022

Background: The morphologic distinction between thymic carcinomas and thymomas, specifically types B3, A, and occasionally micronodular thymomas with lymphoid stroma (MNTLS) can be challenging, as has also been shown in interobserver reproducibility studies. Since thymic carcinomas have a worse prognosis than thymomas, the diagnosis is important for patient management and treatment. This study aimed to identify a panel of immunohistochemical (IHC) markers that aid in the distinction between thymomas and thymic carcinomas in routine practice. Materials and Method: Thymic carcinomas, type A and B3 thymomas, and MNTLS were identified in an institutional database of thymic epithelial tumors (TET) (1963–2021). IHC was performed using antibodies against TdT, Glut-1, CD5, CD117, BAP1, and mTAP. Percent tumor cell staining was recorded (Glut-1, CD5, CD117); loss of expression (BAP1, mTAP) was considered if essentially all tumor cells were negative; TdT was recorded as thymocytes present or absent (including rare thymocytes). Results: 81 specimens included 44 thymomas (25 type A, 11 type B3, 8 MNTLS) and 37 thymic carcinomas (including 24 squamous cell carcinomas). Using BAP1, mTAP, CD117 (cut-off, 10%), and TdT, 88.9% of thymic carcinomas (95.7% of squamous cell carcinomas) and 77.8% of thymomas could be predicted. Glut-1 expression was not found to be useful in that distinction. All tumors that expressed CD5 in ≥50% of tumor cells also expressed CD117 in ≥10% of tumor cells. In four carcinomas with homozygous deletion of CDKN2A, mTAP expression was lost in two squamous cell carcinomas and in a subset of tumor cells of an adenocarcinoma and was preserved in a lymphoepithelial carcinoma. Conclusion: A panel of immunostains including BAP1, mTAP, CD117 (using a cut-off of 10% tumor cell expression), and TdT can be useful in the distinction between thymomas and thymic carcinomas, with only a minority of cases being inconclusive.
Proton Pump Inhibitor Use and Efficacy of Nivolumab and Ipilimumab in Advanced Melanoma
Authors: Homicsko Krisztian , Dummer Reinhard , Hoeller Christoph , Wolchok Jedd D. , Hodi F. Stephen , Larkin James , Ascierto Paolo A. , Atkinson Victoria , Robert Caroline , Postow Michael A. , Re Sandra , Paulucci David , Dobler Darin , Michielin Olivier
Published: May 2022

The impact of proton pump inhibitors (PPIs) on clinical outcomes with first-line immune checkpoint inhibitors (ICIs) in patients with metastatic melanoma was previously analyzed in the phase II study, CheckMate 069. This retrospective analysis utilized data from three phase II/III studies of first-line ICI therapy in untreated advanced melanoma: CheckMate 066, 067, and 069. All randomized patients with PPI use ≤ 30 days before initiating study treatment were included in the PPI-use subgroup. Possible associations between baseline PPI use and efficacy were evaluated within each treatment arm of each study using multivariable modeling. Approximately 20% of 1505 randomized patients across the studies reported baseline PPI use. The median follow-up was 52.6–58.5 months. Objective response rate (ORR), progression-free survival (PFS), and overall survival analyses provided insufficient evidence of a meaningful association between PPI use and efficacy outcomes with nivolumab-plus-ipilimumab, nivolumab, or ipilimumab therapy. In five of the six ICI treatment arms, 95% confidence intervals for odds ratios or hazard ratios traversed 1. Significant associations were observed in the CheckMate 069 combination arm between PPI use and poorer ORR and PFS. This multivariable analysis found insufficient evidence to support meaningful associations between PPI use and ICI efficacy in patients with advanced melanoma.
How to Obtain Maximum Environmental Applicability from Natural Silicates
Authors: Popadić Daliborka , Gavrilov Nemanja , Ignjatović Ljubiša , Krajišnik Danina , Mentus Slavko , Milojević-Rakić Maja , Bajuk-Bogdanović Danica
Published: May 2022

Unmodified natural silicates (bentonite, kaolin, clinoptilolite and diatomites) were tested as adsorbents for the organic pollutants in water tables using Methylene Blue (MB) as the model adsorbate. Among the selected materials, bentonite adsorbed as much as 237 mg/g, confirming its excellent suitability for pollutant removal. Spectral evidence confirmed successful MB immobilization at the bentonite surface. Furthermore, the thermal treatment of MB-saturated adsorbent in an inert atmosphere at 700 °C produced a carbon/silicate composite. EDX confirmed the formation of the nitrogen-doped carbon overlay on the silica scaffold and the obtained composite material was probed as an electrode material for oxygen reduction in an alkaline solution. Reduction proceeded via a two-electron mechanism with the main product being HO2−, a known nucleophile, which was subsequently used to degrade/demethylate MB. The composite showed a considerable 70% MB removal rate after an hour of electrochemical treatment. The synergy between the processes of adsorption of MB and the surface-generated HO2− dictates the efficiency of the method and points to a possible route for spent adsorbent reuse in the form of a durable product for environmental protection.
An Early Disturbance in Serotonergic Neurotransmission Contributes to the Onset of Parkinsonian Phenotypes in Drosophila melanogaster
Authors: Zárate Rafaella V. , Hidalgo Sergio , Navarro Nicole , Molina-Mateo Daniela , Arancibia Duxan , Rojo-Cortés Francisca , Oliva Carlos , Andrés María Estela , Zamorano Pedro , Campusano Jorge M.
Published: May 2022

Parkinson’s disease (PD) is a neurodegenerative disease characterized by motor symptoms and dopaminergic cell loss. A pre-symptomatic phase characterized by non-motor symptoms precedes the onset of motor alterations. Two recent PET studies in human carriers of mutations associated with familial PD demonstrate an early serotonergic commitment—alteration in SERT binding—before any dopaminergic or motor dysfunction, that is, at putative PD pre-symptomatic stages. These findings support the hypothesis that early alterations in the serotonergic system could contribute to the progression of PD, an idea difficult to be tested in humans. Here, we study some components of the serotonergic system during the pre-symptomatic phase in a well-characterized Drosophila PD model, Pink1B9 mutant flies. We detected lower brain serotonin content in Pink1B9 flies, accompanied by reduced activity of SERT before the onset of motor dysfunctions. We also explored the consequences of a brief early manipulation of the serotonergic system in the development of motor symptoms later in aged animals. Feeding young Pink1B9 flies with fluoxetine, a SERT blocker, prevents the loss of dopaminergic neurons and ameliorates motor impairment observed in aged mutant flies. Surprisingly, the same pharmacological manipulation in young control flies results in aged animals exhibiting a PD-like phenotype. Our findings support that an early dysfunction in the serotonergic system precedes and contributes to the onset of the Parkinsonian phenotype in Drosophila.
Data-Driven Mathematical Model of Apoptosis Regulation in Memory Plasma Cells
Authors: Burt Philipp , Cornelis Rebecca , Geißler Gustav , Hahne Stefanie , Radbruch Andreas , Chang Hyun-Dong , Thurley Kevin
Published: May 2022

Memory plasma cells constitutively produce copious amounts of antibodies, imposing a critical risk factor for autoimmune disease. We previously found that plasma cell survival requires secreted factors such as APRIL and direct contact to stromal cells, which act in concert to activate NF-κB- and PI3K-dependent signaling pathways to prevent cell death. However, the regulatory properties of the underlying biochemical network are confounded by the complexity of potential interaction and cross-regulation pathways. Here, based on flow-cytometric quantification of key signaling proteins in the presence or absence of the survival signals APRIL and contact to the stromal cell line ST2, we generated a quantitative model of plasma cell survival. Our model emphasizes the non-redundant nature of the two plasma cell survival signals APRIL and stromal cell contact, and highlights a requirement for differential regulation of individual caspases. The modeling approach allowed us to unify distinct data sets and derive a consistent picture of the intertwined signaling and apoptosis pathways regulating plasma cell survival.
Human Platelet-Rich Plasma Facilitates Angiogenesis to Restore Impaired Uterine Environments with Asherman’s Syndrome for Embryo Implantation and Following Pregnancy in Mice
Authors: Kim Min Kyoung , Yoon Jung Ah , Yoon Sook Young , Park Mira , Lee Woo Sik , Lyu Sang Woo , Song Haengseok
Published: May 2022

Asherman’s syndrome (AS) is caused by intrauterine adhesions and inactive endometrium from repeated curettage of the uterine endometrium. AS is a major cause of recurrent implantation failure and miscarriage and is very difficult to treat because of the poor recovery of endometrial basal cells. Platelet-rich plasma (PRP) has abundant growth factors that may induce angiogenesis and cell proliferation. Here, we demonstrate that human PRP (hPRP) significantly enhances angiogenesis to restore embryo implantation, leading to successful pregnancy in mice with AS. In mice with AS, hPRP treatment considerably reduced the expression of fibrosis markers and alleviated oligo/amenorrhea phenotypes. Mice with AS did not produce any pups, but the hPRP therapy restored their infertility. AS-induced abnormalities, such as aberrantly delayed embryo implantation and intrauterine growth retardation, were considerably eliminated by hPRP. Furthermore, hPRP significantly promoted not only the elevation of various angiogenic factors, but also the migration of endometrial stromal cells. It also increased the phosphorylation of STAT3, a critical mediator of wound healing, and the expression of tissue remodeling genes in a fibrotic uterus. PRP could be a promising therapeutic strategy to promote angiogenesis and reduce fibrosis in impaired uterine environments, leading to successful embryo implantation for better clinical outcomes in patients with AS.
Framework of Intrinsic Immune Landscape of Dormant Prostate Cancer
Authors: Wong Nelson K. Y. , Dong Xin , Lin Yen-Yi , Xue Hui , Wu Rebecca , Lin Dong , Collins Colin , Wang Yuzhuo
Published: May 2022

Androgen deprivation therapy (ADT) is the standard therapy for men with advanced prostate cancer (PCa). PCa often responds to ADT and enters a dormancy period, which can be recognized clinically as a minimal residual disease. However, the majority of these patients will eventually experience a relapse in the form of castration-resistant PCa with poor survival. Therefore, ADT-induced dormancy is a unique time window for treatment that can provide a cure. The study of this well-recognized phase of prostate cancer progression is largely hindered by the scarcity of appropriate clinical tissue and clinically relevant preclinical models. Here, we report the utility of unique and clinically relevant patient-derived xenograft models in the study of the intrinsic immune landscape of dormant PCa. Using data from RNA sequencing, we have reconstructed the immune evasion mechanisms that can be utilized by dormant PCa cells. Since dormant PCa cells need to evade the host immune surveillance for survival, our results provide a framework for further study and for devising immunomodulatory mechanisms that can eliminate dormant PCa cells.
Multinucleated Retinal Pigment Epithelial Cells Adapt to Vision and Exhibit Increased DNA Damage Response
Authors: Ke Qin , Gong Lili , Zhu Xingfei , Qi Ruili , Zou Ming , Chen Baoxin , Liu Wei , Huang Shan , Liu Yizhi , Li David Wan-Cheng
Published: May 2022

Multinucleated retinal pigment epithelium (RPE) cells have been reported in humans and other mammals. Rodents have an extremely high percentage of multinucleated cells (more than 80%). Both mouse and human multinucleated RPE cells exhibit specific regional distributions that are potentially correlated with photoreceptor density. However, detailed investigations of multinucleated RPE in different species and their behavior after DNA damage are missing. Here, we compared the composition of multinucleated RPE cells in nocturnal and diurnal animals that possess distinct rod and cone proportions. We further investigated the reactive oxygen species (ROS) production and DNA damage response in mouse mononucleated and multinucleated RPE cells and determined the effect of p53 dosage on the DNA damage response in these cells. Our results revealed an unrealized association between multinucleated RPE cells and nocturnal vision. In addition, we found multinucleated RPE cells exhibited increased ROS production and DNA damage after X-ray irradiation. Furthermore, haploinsufficiency of p53 led to increased DNA damage frequency after irradiation, and mononucleated RPE cells were more sensitive to a change in p53 dosage. In conclusion, this study provides novel information on in vivo PRE topography and the DNA damage response, which may reflect specific requirements for vision adaption and macular function.
Insight into the Role of the PI3K/Akt Pathway in Ischemic Injury and Post-Infarct Left Ventricular Remodeling in Normal and Diabetic Heart
Authors: Walkowski Bartosz , Kleibert Marcin , Majka Miłosz , Wojciechowska Małgorzata
Published: May 2022

Despite the significant decline in mortality, cardiovascular diseases are still the leading cause of death worldwide. Among them, myocardial infarction (MI) seems to be the most important. A further decline in the death rate may be achieved by the introduction of molecularly targeted drugs. It seems that the components of the PI3K/Akt signaling pathway are good candidates for this. The PI3K/Akt pathway plays a key role in the regulation of the growth and survival of cells, such as cardiomyocytes. In addition, it has been shown that the activation of the PI3K/Akt pathway results in the alleviation of the negative post-infarct changes in the myocardium and is impaired in the state of diabetes. In this article, the role of this pathway was described in each step of ischemia and subsequent left ventricular remodeling. In addition, we point out the most promising substances which need more investigation before introduction into clinical practice. Moreover, we present the impact of diabetes and widely used cardiac and antidiabetic drugs on the PI3K/Akt pathway and discuss the molecular mechanism of its effects on myocardial ischemia and left ventricular remodeling.
Combining Pharmacokinetics and Vibrational Spectroscopy: MCR-ALS Hard-and-Soft Modelling of Drug Uptake In Vitro Using Tailored Kinetic Constraints
Authors: Pérez-Guaita David , Quintás Guillermo , Farhane Zeineb , Tauler Romá , Byrne Hugh J.
Published: May 2022

Raman microspectroscopy is a label-free technique which is very suited for the investigation of pharmacokinetics of cellular uptake, mechanisms of interaction, and efficacies of drugs in vitro. However, the complexity of the spectra makes the identification of spectral patterns associated with the drug and subsequent cellular responses difficult. Indeed, multivariate methods that relate spectral features to the inoculation time do not normally take into account the kinetics involved, and important theoretical information which could assist in the elucidation of the relevant spectral signatures is excluded. Here, we propose the integration of kinetic equations in the modelling of drug uptake and subsequent cellular responses using Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and tailored kinetic constraints, based on a system of ordinary differential equations. Advantages of and challenges to the methodology were evaluated using simulated Raman spectral data sets and real Raman spectra acquired from A549 and Calu-1 human lung cells inoculated with doxorubicin, in vitro. The results suggest a dependency of the outcome on the system of equations used, and the importance of the temporal resolution of the data set to enable the use of complex equations. Nevertheless, the use of tailored kinetic constraints during MCR-ALS allowed a more comprehensive modelling of the system, enabling the elucidation of not only the time-dependent concentration profiles and spectral features of the drug binding and cellular responses, but also an accurate computation of the kinetic constants.
Is P-Glycoprotein Functionally Expressed in the Limiting Membrane of Endolysosomes? A Biochemical and Ultrastructural Study in the Rat Liver
Authors: Gericke Birthe , Wienböker Inka , Brandes Gudrun , Löscher Wolfgang
Published: May 2022

The drug efflux transporter P-glycoprotein (Pgp; ABCB1) plays an important role in drug absorption, disposition, and elimination. There is an ongoing debate whether, in addition to its localization at the plasma membrane, Pgp may also be expressed at the limiting membrane of endolysosomes (ELs), mediating active EL drug sequestration. If true, this would be an important mechanism to prevent drugs from reaching their intracellular targets. However, direct evidence demonstrating the functional expression of Pgp at the limiting membrane of ELs is lacking. This prompted us to perform a biochemical and ultrastructural study on the intracellular localization of Pgp in native rat liver. For this purpose, we established an improved subcellular fractionation procedure for the enrichment of ELs and employed different biochemical and ultrastructural methods to characterize the Pgp localization and function in the enriched EL fractions. Whereas the biochemical methods seemed to indicate that Pgp is functionally expressed at EL limiting membranes, transmission electron microscopy (TEM) indicated that this only occurs rarely, if at all. Instead, Pgp was found in the limiting membrane of early endosomes and intraluminal vesicles. In additional TEM experiments, using a Pgp-overexpressing brain microvessel endothelial cell line (hCMEC/D3-MDR1-EGFP), we examined whether Pgp is expressed at the limiting membrane of ELs when cells are exposed to high levels of the Pgp substrate doxorubicin. Pgp was seen in early endosomes but only rarely in endolysosomes, whereas Pgp immunogold labeling was detected in large autophagosomes. In summary, our data demonstrate the importance of combining biochemical and ultrastructural methods to investigate the relationship between Pgp localization and function.
ANXA11 rs1049550 Associates with Löfgren’s Syndrome and Chronic Sarcoidosis
Authors: Karakaya Bekir , van der Vis Joanne , Veltkamp Marcel , Biesma Douwe , Grutters Jan , van Moorsel Coline
Published: May 2022

Sarcoidosis is an immune mediated granulomatous disease commonly affecting the lungs. Genome wide association studies identified many genomic regions that are shared among multiple immune mediated diseases. However, ANXA11 gene polymorphism rs1049550 is exclusively associated with sarcoidosis, making it a key gene of interest for sarcoidosis disease pathogenesis. However, sarcoidosis is a heterogeneous disease and contradictory findings for ANXA11 have been reported for disease phenotypes. We performed a case–control association study to investigate if ANXA11 associates with benign (Löfgren’s syndrome (LS)) or chronic sarcoidosis and performed a meta-analysis on previously reported findings. A total of 262 sarcoidosis patients, of which 149 had LS and 113 chronic sarcoidosis, and 363 controls were genotyped for rs1049550. Meta-analysis included allele findings for rs1049550 from 6 additional studies. We found a significantly lower T allele frequency in sarcoidosis patients than in healthy controls (0.30 vs. 0.41, respectively, odds ratio (OR) 0.61, 95% confidence interval (CI) 0.48–0.77, p = 3 × 10−5). In LS the T allele frequency of 0.33, and in chronic sarcoidosis the T allele frequency of 0.26 were significantly lower than in healthy controls (OR 0.69, 95% CI 0.52–0.92, p = 0.01 and OR 0.51, 95% CI 0.36–0.70, p = 4 × 10−5, respectively). Meta-analysis including previously published European, African American and Asian cohorts confirmed the association of rs1049550 with sarcoidosis and resulted in a pooled OR of 0.70 (CI 0.66–0.75, p = 3.58 × 10−29). Presence of the T allele of rs1049550 in ANXA11 is protective for sarcoidosis, including benign and chronic phenotypes of the disease.
Focal Liver Lesion MRI Feature Identification Using Efficientnet and MONAI: A Feasibility Study
Authors: Stollmayer Róbert , Budai Bettina Katalin , Rónaszéki Aladár , Zsombor Zita , Kalina Ildikó , Hartmann Erika , Tóth Gábor , Szoldán Péter , Bérczi Viktor , Maurovich-Horvat Pál , Kaposi Pál Novák
Published: May 2022

Liver tumors constitute a major part of the global disease burden, often making regular imaging follow-up necessary. Recently, deep learning (DL) has increasingly been applied in this research area. How these methods could facilitate report writing is still a question, which our study aims to address by assessing multiple DL methods using the Medical Open Network for Artificial Intelligence (MONAI) framework, which may provide clinicians with preliminary information about a given liver lesion. For this purpose, we collected 2274 three-dimensional images of lesions, which we cropped from gadoxetate disodium enhanced T1w, native T1w, and T2w magnetic resonance imaging (MRI) scans. After we performed training and validation using 202 and 65 lesions, we selected the best performing model to predict features of lesions from our in-house test dataset containing 112 lesions. The model (EfficientNetB0) predicted 10 features in the test set with an average area under the receiver operating characteristic curve (standard deviation), sensitivity, specificity, negative predictive value, positive predictive value of 0.84 (0.1), 0.78 (0.14), 0.86 (0.08), 0.89 (0.08) and 0.71 (0.17), respectively. These results suggest that AI methods may assist less experienced residents or radiologists in liver MRI reporting of focal liver lesions.
Long-Distance Repression by Human Silencers: Chromatin Interactions and Phase Separation in Silencers
Authors: Zhang Ying , See Yi Xiang , Tergaonkar Vinay , Fullwood Melissa Jane
Published: May 2022

Three-dimensional genome organization represents an additional layer in the epigenetic regulation of gene expression. Active transcription controlled by enhancers or super-enhancers has been extensively studied. Enhancers or super-enhancers can recruit activators or co-activators to activate target gene expression through long-range chromatin interactions. Chromatin interactions and phase separation play important roles in terms of enhancer or super-enhancer functioning. Silencers are another major type of cis-regulatory element that can mediate gene regulation by turning off or reducing gene expression. However, compared to active transcription, silencer studies are still in their infancy. This review covers the current knowledge of human silencers, especially the roles of chromatin interactions and phase separation in silencers. This review also proposes future directions for human silencer studies.
Allogeneic Serum and Macromolecular Crowding Maintain Native Equine Tenocyte Function in Culture
Authors: Rampin Andrea , Skoufos Ioannis , Raghunath Michael , Tzora Athina , Diakakis Nikolaos , Prassinos Nikitas , Zeugolis Dimitrios I.
Published: May 2022

The absence of a native extracellular matrix and the use of xenogeneic sera are often associated with rapid tenocyte function losses during in vitro culture. Herein, we assessed the influence of different sera (equine serum and foetal bovine serum) on equine tenocyte morphology, viability, metabolic activity, proliferation and protein synthesis as a function of tissue-specific extracellular matrix deposition (induced via macromolecular crowding), aging (passages 3, 6, 9) and time in culture (days 3, 5, 7). In comparison to cells at passage 3, at day 3, in foetal bovine serum and without macromolecular crowding (traditional equine tenocyte culture), the highest number of significantly decreased readouts were observed for cells in foetal bovine serum, at passage 3, at day 5 and day 7 and without macromolecular crowding. Again, in comparison to traditional equine tenocyte culture, the highest number of significantly increased readouts were observed for cells in equine serum, at passage 3 and passage 6, at day 7 and with macromolecular crowding. Our data advocate the use of an allogeneic serum and tissue-specific extracellular matrix for effective expansion of equine tenocytes.
Biosynthesis of Silver Nanoparticles from Cymbopogon citratus Leaf Extract and Evaluation of Their Antimicrobial Properties
Authors: Rakib-Uz-Zaman S M , Hoque Apu Ehsanul , Muntasir Mohammed Nimeree , Mowna Sadrina Afrin , Khanom Mst Gitika , Jahan Shah Saif , Akter Nahid , R. Khan M. Azizur , Shuborna Nadia Sultana , Shams Shahriar Mohd , Khan Kashmery
Published: May 2022

Background: Silver nanoparticles (AgNPs) are toxic to microorganisms and can potentially kill multidrug-resistant bacteria. Nanoparticles can be synthesized in many ways, such as physical or chemical methods. Recently, it has been found that plant molecules can perform the same reduction reactions necessary for the production of nanoparticles but in a much more efficient way. Results: Here, green chemistry was employed to synthesize AgNPs using leaf extracts of Cymbopogon citratus. The effects of different parameters such as temperature, pH, and the volume of plant extract were also tested using their absorbance pattern at different wavelengths. The Surface Plasmon Resonance (SPR) changed with the changes in parameters. Changes in temperature from 20 °C to 60 °C have changed the highest absorbance from 0.972 to 3.893 with an SPR of 470 nm. At higher pH (11.1), the particles become highly unstable and have irregular shapes and sizes. The peak shifts to the right at a lower pH level (3.97), indicating a smaller but unstable compound. We have also investigated the effect of the volume of plant extracts on the reaction time. The sample with the highest amount of plant extract showed the most absorbance with a value of 0.963 at λmax, calculated to be 470 nm. The total formation of the AgNPs was observed visually with a color change from yellow to brownish-black. UV-visible spectroscopy was used to monitor the quantitative formation of AgNPs, showing a signature peak in absorbance between 400 and 500 nm. We have estimated the size of the nanoparticles as 47 nm by comparing the experimental data with the theoretical value using Mieplot. The biosynthesized AgNPs showed enhanced antibacterial activity against several multidrug-resistant bacteria, determined based on the minimal inhibitory concentration and zone of inhibition. Conclusion: The findings of this study indicate that an aqueous extract of C. citratus can synthesize AgNPs when silver nitrate is used as a precursor, and AgNPs act as antimicrobial property enhancers, which can be used to treat antibiotic-resistant bacteria. Hence, mass production and green synthesis of AgNPs from C. citratus will be able to increase the overall health of the general population. Moreover, it will enormously reduce the costs for drug development and provide employment options in the remotely located source areas. Finally, our findings will influence further studies in this field to better understand the properties and applications of AgNPs and ultimately contribute to improving planetary health by increasing immunity with high biocompatibility and less drug toxicity.
Development of a Coelenterazine Derivative with Enhanced Superoxide Anion-Triggered Chemiluminescence in Aqueous Solution
Authors: Silva José Pedro , González-Berdullas Patricia , Esteves da Silva Joaquim C. G. , Pinto da Silva Luís
Published: May 2022

Superoxide anion is a reactive oxygen species (ROS) of biological interest. More specifically, it plays a role in intra- and intercellular signaling, besides being associated with conditions such as inflammation and cancer. Given this, efforts have been made by the research community to devise new sensing strategies for this ROS species. Among them, the chemiluminescent reaction of marine Coelenterazine has been employed as a sensitive and dynamic probing approach. Nevertheless, chemiluminescent reactions are typically associated with lower emissions in aqueous solutions. Herein, here we report the synthesis of a new Coelenterazine derivative with the potential for superoxide anion sensing. Namely, this novel compound is capable of chemiluminescence in a dose-dependent manner when triggered by this ROS species. More importantly, the light-emission intensities provided by this derivative were relevantly enhanced (intensities 2.13 × 101 to 1.11 × 104 times higher) in aqueous solutions at different pH conditions when compared to native Coelenterazine. The half-life of the chemiluminescent signal is also greatly increased for the derivative. Thus, a new chemiluminescence molecule with significant potential for superoxide anion sensing was discovered and reported for the first time.
A Prospective Study of the Serological, Clinical, and Epidemiological Features of a SARS-CoV-2 Positive Pediatric Cohort
Authors: Callejas-Caballero Ignacio , Ruedas-López Alba , Berzosa-Sánchez Arantxa , Illán-Ramos Marta , Joyanes-Abancens Belén , Bodas-Pinedo Andrés , Guillén-Martín Sara , Soto-Sánchez Beatriz , García-Bermejo Isabel , Molina-Arana David , Alós Juan-Ignacio , Baos-Muñoz Elvira , Delgado-Iribarren Alberto , Fuentes-Ferrer Manuel E. , Ramos-Amador José T.
Published: May 2022

Background: SARS-CoV-2 was a global pandemic. Children develop a mild disease and may have a different rate of seroconversion compared to adults. The objective was to determine the number of seronegative patients in a pediatric cohort. We also reviewed the clinical–epidemiological features associated with seroconversion. Methods: A multicenter prospective observational study during September–November 2020, of COVID-19, confirmed by reverse transcription-polymerase chain reaction. Data were obtained 4–8 weeks after diagnosis. Blood samples were collected to investigate the humoral response, using three different serological methods. Results: A total of 111 patients were included (98 symptomatic), 8 were admitted to hospital, none required an Intensive Care Unit visit. Median age: 88 months (IQR: 24–149). Median time between diagnosis and serological test: 37 days (IQR: 34–44). A total of 19 patients were non-seroconverters when using three serological techniques (17.1%; 95% CI: 10.6–25.4); most were aged 2–10 years (35%, p < 0.05). Univariate analysis yielded a lower rate of seroconversion when COVID-19 confirmation was not present amongst household contacts (51.7%; p < 0.05). Conclusions: There was a high proportion of non-seroconverters. This is more commonly encountered in childhood than in adults. Most seronegative patients were in the group aged 2–10 years, and when COVID-19 was not documented in household contacts. Most developed a mild disease. Frequently, children were not the index case within the family.
Ileal Bile Acid Transporter Inhibition Reduces Post-Transplant Diarrhea and Growth Failure in FIC1 Disease—A Case Report
Authors: Ohlendorf Johanna , Goldschmidt Imeke , Junge Norman , Laue Tobias , Nasser Hamoud , Jäckel Elmar , Mutschler Frauke , Pfister Eva-Doreen , Herebian Diran , Keitel Verena , Baumann Ulrich
Published: May 2022

Familial intrahepatic cholestasis 1 (FIC1) disease is a genetic disorder characterized by hepatic and gastrointestinal disease due to ATP8B1 deficiency, often requiring liver transplantation (LT). Extrahepatic symptoms, such as diarrhea, malabsorption, and failure to thrive, do not improve and instead may be aggravated after LT. We describe a patient with FIC1 disease who underwent LT at 2 years, 8 months of age. After LT, the child developed severe refractory diarrhea and failed to thrive. The response to bile acid resins was unsatisfactory, and the parents declined our recommendation for partial external biliary diversion (PEBD). Quality of life was extremely impaired, especially due to severe diarrhea, making school attendance impossible. Attempting to reduce the total bile acids, we initiated off-label use of the ileal bile acid transporter (IBAT) inhibitor Elobixibat (Goofice™), later converted to Odevixibat (Bylvay™). After six months of treatment, the patient showed less stool output, increased weight and height, and improved physical energy levels. The child could now pursue higher undergraduate education. In our patient with FIC1 disease, the use of IBAT inhibitors was effective in treating chronic diarrhea and failure to thrive. This approach is novel; further investigations are needed to clarify the exact mode of action in this condition.
Efficacy of Anakinra on Multiple Coronary Arteries Aneurysms in an Infant with Recurrent Kawasaki Disease, Complicated by Macrophage Activation Syndrome
Authors: Bossi Grazia , Codazzi Alessia Claudia , Vinci Federica , Clerici Edoardo , Regalbuto Corrado , Crapanzano Carmela , Veraldi Daniele , Moiraghi Alice , Marseglia Gian Luigi
Published: May 2022

Kawasaki disease (KD) is rare in infants less than 3 months of age, and its recurrence is exceptional. Infants with KD are at higher risk of severe clinical presentation, therapy failure, complications and coronary aneurysms (CAAs), and this is the reason they deserve more aggressive therapy and a strict clinical follow-up. We report a 2-month-old male with KD, complicated by Macrophage Activation Syndrome (MAS). Despite timely and aggressive therapy with immunoglobulins, steroids and aspirin, multiple CAAs developed. Two-month therapy with anakinra completely reverted all the aneurysms. After six months, the infant experienced KD relapse and was successfully re-treated with immunoglobulins, steroids and aspirin. A strict echocardiographic follow-up did not show recurrence of aneurysms. Two years later, the child is healthy, without cardiac sequelae. In our experience, anakinra was effective in reverting multiple aneurysms and its effect proved to be long-lasting, even in front of KD recurrence. Based on this evidence, it seems reasonable to hypothesize not to limit the use of anakinra as rescue therapy for complicated or refractory KD, but to consider the possibility of adding it to first-line therapies for some subgroups of very-high-risk patients, in order to strengthen the prevention of CAAs.
The North Atlantic Oscillations: Lead–Lag Relations for the NAO, the AMO, and the AMOC—A High-Resolution Lead–lag Analysis
Authors: Seip Knut Lehre , Wang Hui
Published: May 2022

Several studies examine cycle periods and the interactions between the three major climate modes over the North Atlantic, namely the Atlantic meridional overturning circulation (AMOC), the Atlantic multidecadal oscillation (AMO), and the North Atlantic oscillation (NAO). Here, we use a relatively novel high-resolution Lead–lag (LL) method to identify short time windows with persistent LL relations in the three series during the period from 1947 to 2020. We find that there are roughly 20-year time windows where LL relations change direction at both interannual, high-frequency and multidecadal, low-frequency timescales. However, with varying LL strength, the AMO leads AMOC for the full period at the interannual timescale. During the period from 1980 to 2000, we had the sequence NAO→AMO→AMOC→NAO at the interannual timescale. For the full period in the decadal time scale, we obtain NAO→AMO→AMOC. The Ekman variability closely follows the NAO variability. Both single time series and the LL relation between pairs of series show pseudo-oscillating patterns with cycle periods of about 20 years. We list possible mechanisms that contribute to the cyclic behavior, but no conclusive evidence has yet been found.
Effects of the Shot Peening Process on Corrosion Resistance of Aluminum Alloy: A Review
Authors: Huang Hao , Niu Jintao , Xing Xiangtao , Lin Qichao , Chen Hongtang , Qiao Yang
Published: May 2022

The high humidity of marine atmosphere and the existence of corrosive chloride ions lead to the premature corrosion failure of aluminum alloy components. The development of surface-strengthening technology provides an opportunity to prolong their service life spans. As a mature surface-strengthening technology, the shot peening process is widely used, owing to its advantages over other strengthening technologies, including its easy operation and high production rate. The shot-peened surface integrity depends on shot peening variables that introduces the thermomechanical effect to the deformed surface layer. When the inappropriate shot peening parameters are adopted, the shot-peened surface integrity could be deteriorated, which further weakens the corrosion performance of the surface. Therefore, it is essential to optimize shot peening process variables with the consideration of the material and its application. In this paper, the strengthening mechanism of the shot peening process was firstly elaborated, and then the effects of process parameters on the surface integrity of aluminum alloy were reviewed. The relationship between the surface integrity and corrosion resistance was also revealed. Two directions, including the application of the surface temperature rise during the shot peening process and the shot-peened surface roughening, are proposed.
A Variable Attention Nested UNet++ Network-Based NDT X-ray Image Defect Segmentation Method
Authors: Liu Jiayin , Kim Jae Ho
Published: May 2022

In this paper, we describe a new method for non-destructive testing (NDT) X-ray image defect segmentation by introducing a variable attention nested UNet++ network. To further enhance the performance of the faint defect extraction and its clear visibility, a pre-processing method based on pyramid model is also added to the proposed method to effectively perform high dynamic range compression and defect enhancement on the 16-bit raw image. To illustrate its effectiveness and efficiency, we applied the proposed algorithm to the X-ray image defect segmentation problem and carried out extensive experiments. The results support that the proposed method outperforms the existing representative techniques in extracting defect for real X-ray images collected directly from industrial lines, which achieves the better performance with 89.24% IoU, and 94.31% Dice.
Research on High-Temperature Rheological Properties of Emulsified Asphalt Mastics and Their Influencing Factors
Authors: Wang Qing , Chang Haolei , Wang Decai , Hu Shengneng , Wang Pingrang , Zhang Chengshi
Published: May 2022

The high-temperature rheological properties of emulsified asphalt mastics have a significant impact on the service performance of cold recycled mixtures with asphalt emulsions. In this paper, a dynamic shear rheological (DSR) test and a multiple stress creep recovery (MSCR) test are carried out to analyze the influence of tunneling coal gangue powder (TCGP), portland cement (PC), limestone powder (LP), and four kinds of filler binder ratio (F/B) on the high-temperature rheological properties of emulsified asphalt mastics before and after rolling thin film oven test (RTFOT) ageing. Based on the principle of time–temperature equivalence and a viscoelasticity material model, the main curve of emulsified asphalt mastics under frequency scanning test is established, and the rheological properties of emulsified asphalt mastics in a wide frequency domain are analyzed. Finally, the grey entropy theory is used to quantitatively analyze the correlation between different high temperature performance evaluation indices of emulsified asphalt mastics. The results show that the RTFOT ageing process can significantly enhance the high temperature deformation resistance of emulsified asphalt residue and its mastics. The rutting factor (G*/sin δ) of emulsified asphalt mastics increases exponentially with the increase of F/B, while the phase angle is less affected. TCGP mastics and PC mastics have better high temperature performances than those of LP mastics. The most suitable range of F/B is 0.9~1.2 when TCGP is used as the filler, and 1.2~1.5 when PC or LP is used as the filler. Grey entropy correlation analysis shows that there is a good correlation between the two evaluation systems of the DSR test and the MSCR test, and both can evaluate the high-temperature performance of emulsified asphalt mastics.
Uses of Scanning Electrochemical Microscopy (SECM) for the Characterization with Spatial and Chemical Resolution of Thin Surface Layers and Coating Systems Applied on Metals: A Review
Authors: Santana Juan J. , Izquierdo Javier , Souto Ricardo M.
Published: May 2022

Scanning Electrochemical Microscopy (SECM) is increasingly used in the study and characterization of thin surface films as well as organic and inorganic coatings applied on metals for the collection of spatially- and chemically-resolved information on the localized reactions related to material degradation processes. The movement of a microelectrode (ME) in close proximity to the interface under study allows the application of various experimental procedures that can be classified into amperometric and potentiometric operations depending on either sensing faradaic currents or concentration distributions resulting from the corrosion process. Quantitative analysis can be performed using the ME signal, thus revealing different sample properties and/or the influence of the environment and experimental variables that can be observed on different length scales. In this way, identification of the earlier stages for localized corrosion initiation, the adsorption and formation of inhibitor layers, monitoring of water and specific ions uptake by intact polymeric coatings applied on metals for corrosion protection as well as lixiviation, and detection of coating swelling—which constitutes the earlier stages of blistering—have been successfully achieved. Unfortunately, despite these successful applications of SECM for the characterization of surface layers and coating systems applied on metallic materials, we often find in the scientific literature insufficient or even inadequate description of experimental conditions related to the reliability and reproducibility of SECM data for validation. This review focuses specifically on these features as a continuation of a previous review describing the applications of SECM in this field.
Estimation Parameters of Dependence Meta-Analytic Model: New Techniques for the Hierarchical Bayesian Model
Authors: Junaidi  , Nur Darfiana , Hudson Irene , Stojanovski Elizabeth
Published: May 2022

Dependence in meta-analytic models can happen due to the same collected data or from the same researchers. The hierarchical Bayesian linear model in a meta-analysis that allows dependence in effect sizes is investigated in this paper. The interested parameters on the hierarchical Bayesian linear dependence (HBLD) model which was developed using the Bayesian techniques will then be estimated. The joint posterior distribution of all parameters for the hierarchical Bayesian linear dependence (HBLD) model is obtained by applying the Gibbs sampling algorithm. Furthermore, in order to measure the robustness of the HBLD model, the sensitivity analysis is conducted using a different prior distribution on the model. This is carried out by applying the Metropolis within the Gibbs algorithm. The simulation study is performed for the estimation of all parameters in the model. The results show that the obtained estimated parameters are close to the true parameters, indicating the consistency of the parameters for the model. The model is also not sensitive because of the changing prior distribution which shows the robustness of the model. A case study, to assess the effects of native-language vocabulary aids on second language reading, is conducted successfully in testing the parameters of the models.