bluuebunny/crossref_metadata_2025 huggingface dataset:
Adipose Tissue Hypoxia Correlates with Adipokine Hypomethylation and Vascular Dysfunction
Authors: Ali Mohamed M. , Hassan Chandra , Masrur Mario , Bianco Francesco M. , Naquiallah Dina , Mirza Imaduddin , Frederick Patrice , Fernandes Eduardo T. , Giulianotti Cristoforo P. , Gangemi Antonio , Phillips Shane A. , Mahmoud Abeer M.
Published: August 2021

Obesity is characterized by the accumulation of dysfunctional adipose tissues, which predisposes to cardiometabolic diseases. Our previous in vitro studies demonstrated a role of hypoxia in inducing adipokine hypomethylation in adipocytes. We sought to examine this mechanism in visceral adipose tissues (VATs) from obese individuals and its correlation with cardiometabolic risk factors. We propose an involvement of the hypoxia-inducible factor, HIF1α, and the DNA hydroxymethylase, TET1. Blood samples and VAT biopsies were obtained from obese and non-obese subjects (n = 60 each) having bariatric and elective surgeries, respectively. The analyses of VAT showed lower vascularity, and higher levels of HIF1α and TET1 proteins in the obese subjects than controls. Global hypomethylation and hydroxymethylation were observed in VAT from obese subjects along with promoter hypomethylation of several pro-inflammatory adipokines. TET1 protein was enriched near the promotor of the hypomethylated adipokines. The average levels of adipokine methylation correlated positively with vascularity and arteriolar vasoreactivity and negatively with protein levels of HIF1α and TET1 in corresponding VAT samples, serum and tissue inflammatory markers, and other cardiometabolic risk factors. These findings suggest a role for adipose tissue hypoxia in causing epigenetic alterations, which could explain the increased production of adipocytokines and ultimately, vascular dysfunction in obesity.
Picture of the Favourable Immune Profile Induced by Anti-SARS-CoV-2 Vaccination
Authors: Lanuti Paola , Rossi Claudia , Cicalini Ilaria , Pierdomenico Laura , Damiani Verena , Semeraro Daniela , Verrocchio Sara , Del Boccio Piero , Evangelista Adelia , Sarra Annalina , Zucchelli Mirco , Bologna Giuseppina , Simeone Pasquale , Catitti Giulia , Di Marco Federica , Stefanetti Simone , Vespa Simone , Sinjari Bruna , Bucci Ines , De Laurenzi Vincenzo , Di Battista Tonio , Stuppia Liborio , Pieragostino Damiana
Published: August 2021

COVID-19 pandemic has hit people’s health, economy, and society worldwide. Great confidence in returning to normality has been placed in the vaccination campaign. The knowledge of individual immune profiles and the time required to achieve immunological protection is crucial to choose the best vaccination strategy. We compared anti-S1 antibody levels produced over time by BNT162b2 and AZD1222 vaccines and evaluated the induction of antigen-specific T-cells. A total of 2569 anti-SARS-CoV-2 IgG determination on dried blood spot samples were carried out, firstly in a cohort of 1181 individuals at random time-points, and subsequently, in an independent cohort of 88 vaccinated subjects, up to the seventeenth week from the first dose administration. Spike-specific T-cells were analysed in seronegative subjects between the two doses. AZD1222 induced lower anti-S1 IgG levels as compared to BNT162b2. Moreover, 40% of AZD1222 vaccinated subjects and 3% of BNT162b2 individuals resulted in seronegative during all the time-points, between the two doses. All these subjects developed antigen-specific T cells, already after the first dose. These results suggest that this test represents an excellent tool for a wide sero-surveillance. Both vaccines induce a favourable immune profile guaranteeing efficacy against severe adverse effects of SARS-CoV-2 infection, already after the first dose administration.
GRP78 Overexpression Triggers PINK1-IP3R-Mediated Neuroprotective Mitophagy
Authors: Leiva-Rodríguez Tatiana , Romeo-Guitart David , Herrando-Grabulosa Mireia , Muñoz-Guardiola Pau , Polo Miriam , Bañuls Celia , Petegnief Valerie , Bosch Assumpció , Lizcano Jose Miguel , Apostolova Nadezda , Forés Joaquim , Casas Caty
Published: August 2021

An experimental model of spinal root avulsion (RA) is useful to study causal molecular programs that drive retrograde neurodegeneration after neuron-target disconnection. This neurodegenerative process shares common characteristics with neuronal disease-related processes such as the presence of endoplasmic reticulum (ER) stress and autophagy flux blockage. We previously found that the overexpression of GRP78 promoted motoneuronal neuroprotection after RA. After that, we aimed to unravel the underlying mechanism by carrying out a comparative unbiased proteomic analysis and pharmacological and genetic interventions. Unexpectedly, mitochondrial factors turned out to be most altered when GRP78 was overexpressed, and the abundance of engulfed mitochondria, a hallmark of mitophagy, was also observed by electronic microscopy in RA-injured motoneurons after GRP78 overexpression. In addition, GRP78 overexpression increased LC3-mitochondria tagging, promoted PINK1 translocation, mitophagy induction, and recovered mitochondrial function in ER-stressed cells. Lastly, we found that GRP78-promoted pro-survival mitophagy was mediated by PINK1 and IP3R in our in vitro model of motoneuronal death. This data indicates a novel relationship between the GRP78 chaperone and mitophagy, opening novel therapeutical options for drug design to achieve neuroprotection.
Recent Development of Nanomaterials-Based Cytosensors for the Detection of Circulating Tumor Cells
Authors: Sun Zhi-Fang , Chang Yong , Xia Ning
Published: August 2021

The accurate analysis of circulating tumor cells (CTCs) holds great promise in early diagnosis and prognosis of cancers. However, the extremely low abundance of CTCs in peripheral blood samples limits the practical utility of the traditional methods for CTCs detection. Thus, novel and powerful strategies have been proposed for sensitive detection of CTCs. In particular, nanomaterials with exceptional physical and chemical properties have been used to fabricate cytosensors for amplifying the signal and enhancing the sensitivity. In this review, we summarize the recent development of nanomaterials-based optical and electrochemical analytical techniques for CTCs detection, including fluorescence, colorimetry, surface-enhanced Raman scattering, chemiluminescence, electrochemistry, electrochemiluminescence, photoelectrochemistry and so on.
Rebuilding Body–Brain Interaction from the Vagal Network in Spinal Cord Injuries
Authors: De Martino Maria Luisa , De Bartolo Mina , Leemhuis Erik , Pazzaglia Mariella
Published: August 2021

Spinal cord injuries (SCIs) exert devastating effects on body awareness, leading to the disruption of the transmission of sensory and motor inputs. Researchers have attempted to improve perceived body awareness post-SCI by intervening at the multisensory level, with the integration of somatic sensory and motor signals. However, the contributions of interoceptive-visceral inputs, particularly the potential interaction of motor and interoceptive signals, remain largely unaddressed. The present perspective aims to shed light on the use of interoceptive signals as a significant resource for patients with SCI to experience a complete sense of body awareness. First, we describe interoceptive signals as a significant obstacle preventing such patients from experiencing body awareness. Second, we discuss the multi-level mechanisms associated with the homeostatic stability of the body, which creates a unified, coherent experience of one’s self and one’s body, including real-time updates. Body awareness can be enhanced by targeting the vagus nerve function by, for example, applying transcutaneous vagus nerve stimulation. This perspective offers a potentially useful insight for researchers and healthcare professionals, allowing them to be better equipped in SCI therapy. This will lead to improved sensory motor and interoceptive signals, a decreased likelihood of developing deafferentation pain, and the successful implementation of modern robotic technologies.
Maternal Immune Activation Causes Social Behavior Deficits and Hypomyelination in Male Rat Offspring with an Autism-Like Microbiota Profile
Authors: Lee Gilbert Aaron , Lin Yen-Kuang , Lai Jing-Huei , Lo Yu-Chun , Yang Yu-Chen S. H. , Ye Syuan-You , Lee Chia-Jung , Wang Ching-Chiung , Chiang Yung-Hsiao , Tseng Sung-Hui
Published: August 2021

Maternal immune activation (MIA) increases the risk of autism spectrum disorder (ASD) in offspring. Microbial dysbiosis is associated with ASD symptoms. However, the alterations in the brain–gut–microbiota axis in lipopolysaccharide (LPS)-induced MIA offspring remain unclear. Here, we examined the social behavior, anxiety-like and repetitive behavior, microbiota profile, and myelination levels in LPS-induced MIA rat offspring. Compared with control offspring, MIA male rat offspring spent less time in an active social interaction with stranger rats, displayed more anxiety-like and repetitive behavior, and had more hypomyelination in the prefrontal cortex and thalamic nucleus. A fecal microbiota analysis revealed that MIA offspring had a higher abundance of Alistipes, Fusobacterium, and Ruminococcus and a lower abundance of Coprococcus, Erysipelotrichaies, and Actinobacteria than control offspring, which is consistent with that of humans with ASD. The least absolute shrinkage and selection operator (LASSO) method was applied to determine the relative importance of the microbiota, which indicated that the abundance of Alistipes and Actinobacteria was the most relevant for the profile of defective social behavior, whereas Fusobacterium and Coprococcus was associated with anxiety-like and repetitive behavior. In summary, LPS-induced MIA offspring showed an abnormal brain–gut–microbiota axis with social behavior deficits, anxiety-like and repetitive behavior, hypomyelination, and an ASD-like microbiota profile.
An Analysis of the Multifaceted Roles of Heme in the Pathogenesis of Cancer and Related Diseases
Authors: Wang Tianyuan , Ashrafi Adnin , Modareszadeh Pouya , Deese Alexander R. , Chacon Castro Maria Del Carmen , Alemi Parinaz Sadat , Zhang Li
Published: August 2021

Heme is an essential prosthetic group in proteins and enzymes involved in oxygen utilization and metabolism. Heme also plays versatile and fascinating roles in regulating fundamental biological processes, ranging from aerobic respiration to drug metabolism. Increasing experimental and epidemiological data have shown that altered heme homeostasis accelerates the development and progression of common diseases, including various cancers, diabetes, vascular diseases, and Alzheimer’s disease. The effects of heme on the pathogenesis of these diseases may be mediated via its action on various cellular signaling and regulatory proteins, as well as its function in cellular bioenergetics, specifically, oxidative phosphorylation (OXPHOS). Elevated heme levels in cancer cells intensify OXPHOS, leading to higher ATP generation and fueling tumorigenic functions. In contrast, lowered heme levels in neurons may reduce OXPHOS, leading to defects in bioenergetics and causing neurological deficits. Further, heme has been shown to modulate the activities of diverse cellular proteins influencing disease pathogenesis. These include BTB and CNC homology 1 (BACH1), tumor suppressor P53 protein, progesterone receptor membrane component 1 protein (PGRMC1), cystathionine-β-synthase (CBS), soluble guanylate cyclase (sGC), and nitric oxide synthases (NOS). This review provides an in-depth analysis of heme function in influencing diverse molecular and cellular processes germane to disease pathogenesis and the modes by which heme modulates the activities of cellular proteins involved in the development of cancer and other common diseases.
Is the Morphological Subtype of Extra-Pulmonary Neuroendocrine Carcinoma Clinically Relevant?
Authors: Frizziero Melissa , Durand Alice , Taboada Rodrigo G. , Zaninotto Elisa , Luchini Claudio , Chakrabarty Bipasha , Hervieu Valérie , Claro Laura C. L. , Zhou Cong , Cingarlini Sara , Milella Michele , Walter Thomas , Riechelmann Rachel S. , Lamarca Angela , Hubner Richard A. , Mansoor Wasat , Valle Juan W. , McNamara Mairéad G.
Published: August 2021

Extra-pulmonary neuroendocrine carcinomas (EP-NECs) are lethal cancers with limited treatment options. Identification of contributing factors to the observed heterogeneity of clinical outcomes within the EP-NEC family is warranted, to enable identification of effective treatments. A multicentre retrospective study investigated potential differences in “real-world” treatment/survival outcomes between small-cell (SC) versus (vs.) non-SC EP-NECs. One-hundred and seventy patients were included: 77 (45.3%) had SC EP-NECs and 93 (54.7%) had non-SC EP-NECs. Compared to the SC subgroup, the non-SC subgroup had the following features: (1) a lower mean Ki-67 index (69.3% vs. 78.7%; p = 0.002); (2) a lower proportion of cases with a Ki-67 index of ≥55% (73.9% vs. 88.7%; p = 0.025); (3) reduced sensitivity to first-line platinum/etoposide (objective response rate: 31.6% vs. 55.1%, p = 0.015; and disease control rate; 59.7% vs. 79.6%, p = 0.027); (4) worse progression-free survival (PFS) (adjusted-HR = 1.615, p = 0.016) and overall survival (OS) (adjusted-HR = 1.640, p = 0.015) in the advanced setting. Within the advanced EP-NEC cohort, subgroups according to morphological subtype and Ki-67 index (<55% vs. ≥55%) had significantly different PFS (adjusted-p = 0.021) and OS (adjusted-p = 0.051), with the non-SC subgroup with a Ki-67 index of <55% and non-SC subgroup with a Ki-67 index of ≥55% showing the best and worst outcomes, respectively. To conclude, the morphological subtype of EP-NEC provides complementary information to the Ki-67 index and may aid identification of patients who could benefit from alternative first-line treatment strategies to platinum/etoposide.
Pan-Cancer Analysis of Prognostic and Immune Infiltrates for CXCs
Authors: Li Long , Yao Wenchao , Yan Sen , Dong Xianghui , Lv Zhenyi , Jing Qingxu , Wang Qiang , Ma Biao , Hao Chenjun , Xue Dongbo , Wang Dawei
Published: August 2021

Background: CXCs are important genes that regulate inflammation and tumor metastasis. However, the expression level, prognosis value, and immune infiltration of CXCs in cancers are not clear. Methods: Multiple online datasets were used to analyze the expression, prognosis, and immune regulation of CXCs in this study. Network analysis of the Amadis database and GEO dataset was used to analyze the regulation of intestinal flora on the expression of CXCs. A mouse model was used to verify the fact that intestinal bacterial dysregulation can affect the expression of CXCs. Results: In the three cancers, multiple datasets verified the fact that the mRNA expression of this family was significantly different; the mRNA levels of CXCL3, 8, 9, 10, 14, and 17 were significantly correlated with the prognosis of three cancers. CXCs were correlated with six types of immuno-infiltrating cells in three cancers. Immunohistochemistry of clinical samples confirmed that the expression of CXCL8 and 10 was higher in three cancer tissues. Animal experiments have shown that intestinal flora dysregulation can affect CXCL8 and 10 expressions. Conclusion: Our results further elucidate the function of CXCs in cancers and provide new insights into the prognosis and immune infiltration of breast, colon, and pancreatic cancers, and they suggest that intestinal flora may influence disease progression through CXCs.
Human SMAD4 Genomic Variants Identified in Individuals with Heritable and Early-Onset Thoracic Aortic Disease
Authors: Bhave Shreyas A. , Guo Dongchuan , Angelov Stoyan N. , Bamshad Michael J. , Nickerson Deborah A. , Milewicz Dianna M. , Wallingford Mary C.
Published: August 2021

Thoracic aortic aneurysms (TAAs) that progress to acute thoracic aortic dissections (TADs) are life-threatening vascular events that have been associated with altered transforming growth factor (TGF) β signaling. In addition to TAA, multiple genetic vascular disorders, including hereditary hemorrhagic telangiectasia (HHT), involve altered TGFβ signaling and vascular malformations. Due to the importance of TGFβ, genomic variant databases have been curated for activin receptor-like kinase 1 (ALK1) and endoglin (ENG). This case report details seven variants in SMAD4 that are associated with either heritable or early-onset aortic dissections and compares them to pathogenic exon variants in gnomAD v2.1.1. The TAA and TAD variants were identified through whole exome sequencing of 346 families with unrelated heritable thoracic aortic disease (HTAD) and 355 individuals with early-onset (age ≤ 56 years old) thoracic aortic dissection (ESTAD). An allele frequency filter of less than 0.05% was applied in the Genome Aggregation Database (gnomAD exome v2.1.1) with a combined annotation-dependent depletion score (CADD) greater than 20. These seven variants also have a higher REVEL score (>0.2), indicating pathogenic potential. Further in vivo and in vitro analysis is needed to evaluate how these variants affect SMAD4 mRNA stability and protein activity in association with thoracic aortic disease.
Two (Chemo)-Enzymatic Cascades for the Production of Opposite Enantiomers of Chiral Azidoalcohols
Authors: Calderini Elia , Süss Philipp , Hollmann Frank , Wardenga Rainer , Schallmey Anett
Published: August 2021

Multi-step cascade reactions have gained increasing attention in the biocatalysis field in recent years. In particular, multi-enzymatic cascades can achieve high molecular complexity without workup of reaction intermediates thanks to the enzymes’ intrinsic selectivity; and where enzymes fall short, organo- or metal catalysts can further expand the range of possible synthetic routes. Here, we present two enantiocomplementary (chemo)-enzymatic cascades composed of either a styrene monooxygenase (StyAB) or the Shi epoxidation catalyst for enantioselective alkene epoxidation in the first step, coupled with a halohydrin dehalogenase (HHDH)-catalysed regioselective epoxide ring opening in the second step for the synthesis of chiral aliphatic non-terminal azidoalcohols. Through the controlled formation of two new stereocenters, corresponding azidoalcohol products could be obtained with high regioselectivity and excellent enantioselectivity (99% ee) in the StyAB-HHDH cascade, while product enantiomeric excesses in the Shi-HHDH cascade ranged between 56 and 61%.
Design of Silica Nanoparticles-Supported Metal Catalyst by Wet Impregnation with Catalytic Performance for Tuning Carbon Nanotubes Growth
Authors: da Cunha Tairan , Maulu Alberto , Guillot Jérôme , Fleming Yves , Duez Benoit , Lenoble Damien , Arl Didier
Published: August 2021

The catalytic activity of cobalt and iron nanoparticles for the growth of carbon nanotubes (CNTs) was studied by a specific reproducible and up-scalable fabrication method. Co and Fe catalysts were deposited over SiO2 nanoparticles by a wet-impregnation method and two different annealing steps were applied for the catalyst formation/activation. The samples were calcined at an optimal temperature of 450 °C resulting in the formation of metal oxide nano-islands without the detection of silicates. Further reduction treatment (700 °C) under H2 successfully converted oxide nanoparticles to Co and Fe metallic species. Furthermore, the catalytic efficiency of both supported-metal nanoparticles at 2 and 5% in weight of silica was evaluated through the growth of CNTs. The CNT structure, morphology and size dispersion were tailored according to the metal catalyst concentration.
Aerobic Oxidative Desulfurization of Liquid Fuel Catalyzed by P–Mo–V Heteropoly Acids in the Presence of Aldehyde
Authors: Ghubayra Reem , Hindle Rachel , Yahya Rana , Kozhevnikova Elena F. , Kozhevnikov Ivan V.
Published: August 2021

Aerobic oxidative desulfurization (ODS) of model liquid fuel (dodecane spiked with dibenzothiophene (DBT)) was carried out in the presence of bulk and supported Keggin-type heteropoly acids H3+nPMo12-nVnO40 (HPA-n, n = 0–3) as heterogeneous catalysts and benzaldehyde as a sacrificial reductant. In the presence of bulk H4PMo11VO40 (HPA-1), 100% of DBT was removed from fuel (converted to DBT sulfone) at 60 °C and ambient air pressure. Multiple catalyst reuse without loss of activity was demonstrated. The ODS reaction was strongly inhibited by radical scavengers. An unbranched radical chain mechanism was proposed.
The Activity Enhancement Effect of Ionic Liquids on Oxygen Reduction Reaction Catalysts: From Rotating Disk Electrode to Membrane Electrode Assembly
Authors: Huang Kan , Morales-Collazo Oscar , Chen Zhichao , Song Tangqiumei , Wang Liang , Lin Honghong , Brennecke Joan F. , Jia Hongfei
Published: August 2021

Ionic liquids (ILs) have been explored as a surface modification strategy to promote the oxygen reduction reaction (ORR) on Pt/C and their chemical structures were identified to have strong influence on the ORR activities. To better understand the roles of anion and cation of ILs on the catalytic reaction, two cations ([MTBD]+ and [bmim]+) were paired with three anions ([TFSI]−, [beti]−, and [C4F9SO3]−) to form various IL structures. By systematically varying the IL combinations and studying their effects on the electrochemical behaviors, such as electrochemical surface area and specific ORR activities, it was found that cation structure had a higher influence than anion, and the impact of the [MTBD]+ series was stronger than the [bmim]+ series. In addition to the investigation in the half-cell, studies were also extended to the membrane electrode assembly (MEA). Considerable performance enhancements were demonstrated in both the kinetic region and high current density region with the aid of IL. This work suggests that IL modification can provide a complementary approach to improve the performance of proton exchange membrane fuel cells.
On the Effect of the M3+ Origin on the Properties and Aldol Condensation Performance of MgM3+ Hydrotalcites and Mixed Oxides
Authors: Korolova Valeriia , Kikhtyanin Oleg , Veselý Martin , Vrtiška Dan , Paterová Iva , Fíla Vlastimil , Čapek Libor , Kubička David
Published: August 2021

Hydrotalcites (HTCs) are promising solid base catalysts to produce advanced biofuels by aldol condensation. Their main potential lies in the tunability of their acid-base properties by varying their composition. However, the relationship between the composition of hydrotalcites, their basicity, and their catalytic performance has not yet been fully revealed. Here, we investigate systematically the preparation of HTCs with the general formula of Mg6M3+2(OH)16CO3·4H2O, where M3+ stands for Al, Ga, Fe, and In, while keeping the Mg/M3+ equal to 3. We use an array of analytical methods including XRD, N2 physisorption, CO2-TPD, TGA-MS, FTIR-ATR, and SEM to assess changes in the properties and concluded that the nature of M3+ affected the HTC crystallinity. We show that the basicity of the HTC-derived mixed oxides decreased with the increase in atomic weight of M3+, which was reflected by decreased furfural conversion in its aldol condensation with acetone. We demonstrate that all MgM3+ mixed oxides can be fully rehydrated, which boosted their activity in aldol condensation. Taking all characterization results together, we conclude that the catalytic performance of the rehydrated HTCs is determined by the “host” MgO component, rather than the nature of M3+.
A Comprehensive Assessment of Catalytic Performances of Mn2O3 Nanoparticles for Peroxymonosulfate Activation during Bisphenol A Degradation
Authors: Chen Li , Fu Wanyi , Hou Congyu , Yang Yulong , Zhang Xihui
Published: August 2021

Catalytic performances of Mn2O3 nanoparticles for peroxymonosulfate (PMS) activation in bisphenol A (BPA) degradation were comprehensively investigated in this study. Experimental results showed that 10 mg/L BPA could be 100% degraded within 20 min with the dosages of 0.2 g/L Mn2O3 and 0.1 mM PMS. Moreover, Mn2O3 showed remarkable activity in activation of PMS and excellent adaptability in various real water matrices, including river water, tap water and secondary effluents. Based on the radical detection and scavenging experiments, it was found that both radical and non-radical oxidation contributed to the degradation of BPA and 1O2 was the dominant species in the degradation compared to •OH, SO4•− and O2•−. A total of 15 transformation products were identified by LC/MS-MS during BPA degradation in the Mn2O3/PMS system, and degradation pathways via three routes are proposed. Compared with lab-made catalysts reported in the literature, the Mn2O3 catalyst demonstrated its superiority in terms of its high TOC removal, low PMS consumption and fast degradation rate for BPA.
A Novel Treatment for Glomerular Disease: Targeting the Activated Macrophage Folate Receptor with a Trojan Horse Therapy in Rats
Authors: Garcia Gabriela E. , Lu Yingjuan J. , Truong Luan D. , Roncal-Jiménez Carlos A. , Miyazaki Makoto , Miyazaki-Anzai Shinobu , Cara-Fuentes Gabriel , Andres-Hernando Ana , Lanaspa Miguel , Johnson Richard J. , Leamon Christopher P.
Published: August 2021

Since activated macrophages express a functional folate receptor β (FRβ), targeting this macrophage population with folate-linked drugs could increase selectivity to treat inflammatory diseases. Using a macrophage-mediated anti-glomerular basement membrane (anti-GBM) glomerulonephritis (GN) in WKY rats, we investigated the effect of a novel folic acid-aminopterin (AMT) conjugate (EC2319) designed to intracellularly deliver AMT via the FR. We found that treatment with EC2319 significantly attenuated kidney injury and preserved renal function. Kidney protection with EC2319 was blocked by a folate competitor, indicating that its mechanism of action was specifically FRβ-mediated. Notably, treatment with methotrexate (MTX), another folic acid antagonist related to AMT, did not protect from kidney damage. EC2319 reduced glomerular and interstitial macrophage infiltration and decreased M1 macrophage recruitment but not M2 macrophages. The expression of CCL2 and the pro-fibrotic cytokine TGF-β were also reduced in nephritic glomeruli with EC2319 treatment. In EC2319-treated rats, there was a significant decrease in the deposition of collagens. In nephritic kidneys, FRβ was expressed on periglomerular macrophages and macrophages present in the crescents, but its expression was not observed in normal kidneys. These data indicate that selectively targeting the activated macrophage population could represent a novel means for treating anti-GBM GN and other acute crescentic glomerulonephritis.
Selective Autophagy in Hyperglycemia-Induced Microvascular and Macrovascular Diseases
Authors: Bharath Leena P. , Rockhold Jack Donato , Conway Rachel
Published: August 2021

Dysregulation of autophagy is an important underlying cause in the onset and progression of many metabolic diseases, including diabetes. Studies in animal models and humans show that impairment in the removal and the recycling of organelles, in particular, contributes to cellular damage, functional failure, and the onset of metabolic diseases. Interestingly, in certain contexts, inhibition of autophagy can be protective. While the inability to upregulate autophagy can play a critical role in the development of diseases, excessive autophagy can also be detrimental, making autophagy an intricately regulated process, the altering of which can adversely affect organismal health. Autophagy is indispensable for maintaining normal cardiac and vascular structure and function. Patients with diabetes are at a higher risk of developing and dying from vascular complications. Autophagy dysregulation is associated with the development of heart failure, many forms of cardiomyopathy, atherosclerosis, myocardial infarction, and microvascular complications in diabetic patients. Here, we review the recent findings on selective autophagy in hyperglycemia and diabetes-associated microvascular and macrovascular complications.
Cognitive Impairment in Frail Hypertensive Elderly Patients: Role of Hyperglycemia
Authors: Mone Pasquale , Gambardella Jessica , Pansini Antonella , de Donato Antonio , Martinelli Giuseppe , Boccalone Eugenio , Matarese Alessandro , Frullone Salvatore , Santulli Gaetano
Published: August 2021

Endothelial dysfunction is a key hallmark of hypertension, which is a leading risk factor for cognitive decline in older adults with or without frailty. Similarly, hyperglycemia is known to impair endothelial function and is a predictor of severe cardiovascular outcomes, independent of the presence of diabetes. On these grounds, we designed a study to assess the effects of high-glucose and metformin on brain microvascular endothelial cells (ECs) and on cognitive impairment in frail hypertensive patients. We tested the effects of metformin on high-glucose-induced cell death, cell permeability, and generation of reactive oxygen species in vitro, in human brain microvascular ECs. To investigate the consequences of hyperglycemia and metformin in the clinical scenario, we recruited frail hypertensive patients and we evaluated their Montreal Cognitive Assessment (MoCA) scores, comparing them according to the glycemic status (normoglycemic vs. hyperglycemic) and the use of metformin. We enrolled 376 patients, of which 209 successfully completed the study. We observed a significant correlation between MoCA score and glycemia. We found that hyperglycemic patients treated with metformin had a significantly better MoCA score than hyperglycemic patients treated with insulin (18.32 ± 3.9 vs. 14.94 ± 3.8; p < 0.001). Our in vitro assays confirmed the beneficial effects of metformin on human brain microvascular ECs. To our knowledge, this is the first study correlating MoCA score and glycemia in frail and hypertensive older adults, showing that hyperglycemia aggravates cognitive impairment.
High-Fat Diet Alters the Retinal Transcriptome in the Absence of Gut Microbiota
Authors: Dao David , Xie Bingqing , Nadeem Urooba , Xiao Jason , Movahedan Asad , D’Souza Mark , Leone Vanessa , Hariprasad Seenu M. , Chang Eugene B. , Sulakhe Dinanath , Skondra Dimitra
Published: August 2021

The relationship between retinal disease, diet, and the gut microbiome has shown increasing importance over recent years. In particular, high-fat diets (HFDs) are associated with development and progression of several retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy. However, the complex, overlapping interactions between diet, gut microbiome, and retinal homeostasis are poorly understood. Using high-throughput RNA-sequencing (RNA-seq) of whole retinas, we compare the retinal transcriptome from germ-free (GF) mice on a regular diet (ND) and HFD to investigate transcriptomic changes without influence of gut microbiome. After correction of raw data, 53 differentially expressed genes (DEGs) were identified, of which 19 were upregulated and 34 were downregulated in GF-HFD mice. Key genes involved in retinal inflammation, angiogenesis, and RPE function were identified. Enrichment analysis revealed that the top 3 biological processes affected were regulation of blood vessel diameter, inflammatory response, and negative regulation of endopeptidase. Molecular functions altered include endopeptidase inhibitor activity, protease binding, and cysteine-type endopeptidase inhibitor activity. Human and mouse pathway analysis revealed that the complement and coagulation cascades are significantly affected by HFD. This study demonstrates novel data that diet can directly modulate the retinal transcriptome independently of the gut microbiome.
β-Adrenergic Stimulation Synchronizes a Broad Spectrum of Action Potential Firing Rates of Cardiac Pacemaker Cells toward a Higher Population Average
Authors: Kim Mary S. , Monfredi Oliver , Maltseva Larissa A. , Lakatta Edward G. , Maltsev Victor A.
Published: August 2021

The heartbeat is initiated by pacemaker cells residing in the sinoatrial node (SAN). SAN cells generate spontaneous action potentials (APs), i.e., normal automaticity. The sympathetic nervous system increases the heart rate commensurate with the cardiac output demand via stimulation of SAN β-adrenergic receptors (βAR). While SAN cells reportedly represent a highly heterogeneous cell population, the current dogma is that, in response to βAR stimulation, all cells increase their spontaneous AP firing rate in a similar fashion. The aim of the present study was to investigate the cell-to-cell variability in the responses of a large population of SAN cells. We measured the βAR responses among 166 single SAN cells isolated from 33 guinea pig hearts. In contrast to the current dogma, the SAN cell responses to βAR stimulation substantially varied. In each cell, changes in the AP cycle length were highly correlated (R2 = 0.97) with the AP cycle length before βAR stimulation. While, as expected, on average, the cells increased their pacemaker rate, greater responses were observed in cells with slower basal rates, and vice versa: cells with higher basal rates showed smaller responses, no responses, or even decreased their rate. Thus, βAR stimulation synchronized the operation of the SAN cell population toward a higher average rate, rather than uniformly shifting the rate in each cell, creating a new paradigm of βAR-driven fight-or-flight responses among individual pacemaker cells.
Highly Sensitive Quartz-Based Sensing System for the Detection of Subpercentage Changes in the Relative Permittivity of Liquids Flowing in Microchannels
Authors: Matko Vojko , Milanovič Miro
Published: August 2021

We describe a highly sensitive quartz sensor for measuring changes in the relative permittivity of liquids flowing in microchannels. The proposed method uses a highly stable oscillator and capacitance-dependent quartz crystal together with a capacitance-sensitive element attached along the microchannel. A change in the relative permittivity of the fluid induces a change in the capacitance of the sensitive element in the aF range, which is detected as a change in the resonant frequency. The advantages of the proposed measurement technique are the extreme sensitivity (changes in the relative permittivity as low as 0.01% can be detected), the temperature independence of the setup between 10 and 40 °C, the stability (the frequency reading fluctuates within 0.025 Hz), and the low cost compared with the methods that use impedance analyzers or lock-in amplifiers. We present the use of the method to detect changes in mixtures of liquids if the temperature, volume fractions, or properties of one liquid change. The method presents a useful tool for applications in biology, chemistry, pharmacy, and technology in general wherever accurate monitoring of compositions of fluids is required and where changes, for example, due to temperature variation or mixture aging, need to be detected in real time.
The Role of Environmental Risk Factors on the Development of Childhood Allergic Rhinitis
Authors: Wu Allison C. , Dahlin Amber , Wang Alberta L.
Published: August 2021

Environmental factors play an important role in the development and exacerbation of allergic rhinitis (AR) in childhood. Indoor air pollution, such as house dust mites and secondhand smoke, can significantly increase the onset of AR, while pet dander may affect the exacerbation of AR symptoms in children. Furthermore, traffic related air pollution and pollen are outdoor air pollutants that can affect immune competency and airway responsiveness, increasing the risk of AR in children. Climate change has increased AR in children, as growth patterns of allergenic species have changed, resulting in longer pollen seasons. More extreme and frequent weather events also contribute to the deterioration of indoor air quality due to climate change. Additionally, viruses provoke respiratory tract infections, worsening the symptoms of AR, while viral infections alter the immune system. Although viruses and pollution influence development and exacerbation of AR, a variety of treatment and prevention options are available for AR patients. The protective influence of vegetation (greenness) is heavily associated with air pollution mitigation, relieving AR exacerbations, while the use of air filters can reduce allergic triggers. Oral antihistamines and intranasal corticosteroids are common pharmacotherapy for AR symptoms. In this review, we discuss the environmental risk factors for AR and summarize treatment strategies for preventing and managing AR in children.
Management of Central Precocious Puberty in Children with Hypothalamic Hamartoma
Authors: Suh Junghwan , Choi Youngha , Oh Jun Suk , Song Kyungchul , Choi Han Saem , Kwon Ahreum , Chae Hyun Wook , Kim Ho-Seong
Published: August 2021

Hypothalamic hamartoma (HH) is a rare, congenital, and benign lesion of the tuber cinereum, typically presenting with central precocious puberty (CPP), gelastic seizure, and developmental delay. This study aimed to investigate CPP in HH patients and compare clinical features between before and after gonadotropin-releasing hormone (GnRH) agonist treatment. A total of 30 HH patients under 18 years of age who visited Severance Children’s Hospital between January 2005 and May 2020 were retrospectively reviewed. Fourteen patients were male (46.7%) and sixteen (53.3%) were female, with a mean age at diagnosis was4.2 ± 2.9 years. During follow-up, 24 patients (80.0%) were diagnosed with CPP, 15 patients (50.0%) had gelastic seizure, and 13 patients (43.3%) had developmental delay. The gelastic seizure was significantly associated with sessile type HH rather than pedunculated type HH (85.7% vs. 18.8%, p = 0.001). After GnRH agonist treatment, discrepancies between bone age and chronological age decreased (3.3 ± 1.3 years to 2.0 ± 1.7 years, p = 0.002). Additionally, height standard deviation score for bone age was increased, and predicted adult height increased significantly in females, while males showed an increasing trend. Clinical symptoms of HH were closely associated with the location of HH, and GnRH agonist treatment was safe and effective in the management of CPP caused by HH.
Assessment and Clinical Utility of a Non-Next-Generation Sequencing-Based Non-Invasive Prenatal Testing Technology
Authors: Gormus Uzay , Chaubey Alka , Shenoy Suresh , Wong Yong Wee , Chan Lee Yin , Choo Bao Ping , Oraha Liza , Gousseva Anna , Persson Fredrik , Prensky Lawrence , Chin Ephrem , Hegde Madhuri
Published: August 2021

Background: Rolling-circle replication (RCR) is a novel technology that has not been applied to cell-free DNA (cfDNA) testing until recently. Given the cost and simplicity advantages of this technology compared to other platforms currently used in cfDNA analysis, an assessment of RCR in clinical laboratories was performed. Here, we present the first validation study from clinical laboratories utilizing RCR technology. Methods: 831 samples from spontaneously pregnant women carrying a singleton fetus, and 25 synthetic samples, were analyzed for the fetal risk of trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13), by three laboratories on three continents. All the screen-positive pregnancies were provided post-test genetic counseling and confirmatory diagnostic invasive testing (e.g., amniocentesis). The screen-negative pregnancies were routinely evaluated at birth for fetal aneuploidies, using newborn examinations, and any suspected aneuploidies would have been offered diagnostic testing or confirmed with karyotyping. Results: The study found rolling-circle replication to be a highly viable technology for the clinical assessment of fetal aneuploidies, with 100% sensitivity for T21 (95% CI: 82.35–100.00%); 100.00% sensitivity for T18 (71.51–100.00%); and 100.00% sensitivity for T13 analyses (66.37–100.00%). The specificities were >99% for each trisomy (99.7% (99.01–99.97%) for T21; 99.5% (98.62–99.85%) for T18; 99.7% (99.03–99.97%) for T13), along with a first-pass no-call rate of 0.93%. Conclusions: The study showed that using a rolling-circle replication-based cfDNA system for the evaluation of the common aneuploidies would provide greater accuracy and clinical utility compared to conventional biochemical screening, and it would provide comparable results to other reported cfDNA methodologies.
The Influence of Sodium Tungstate Concentration on the Electrode Reactions at Iron–Tungsten Alloy Electrodeposition
Authors: Belevskii Stanislav , Silkin Serghei , Tsyntsaru Natalia , Cesiulis Henrikas , Dikusar Alexandr
Published: August 2021

The investigation of Fe-W alloys is growing in comparison to other W alloys with iron group metals due to the environmental and health issues linked to Ni and Co materials. The influence of Na2WO4 concentration in the range 0 to 0.5 M on bath chemistry and electrode reactions on Pt in Fe-W alloys’ electrodeposition from citrate electrolyte was investigated by means of rotating disk electrode (RDE) and cyclic voltammetry (CV) synchronized with electrochemical quartz crystal microbalance (EQCM). Depending on species distribution, the formation of Fe-W alloys becomes thermodynamically possible at potentials less than −0.87 V to −0.82 V (vs. Ag/AgCl). The decrease in electrode mass during cathodic current pass in the course of CV recording was detected by EQCM and explained. The overall electrode process involving Fe-W alloy formation may be described using formalities of mixed kinetics. The apparent values of kinetic and diffusion currents linearly depend on the concentration of Na2WO4. Based on the values of partial currents for Fe and W, it was concluded that codeposition of Fe-W alloy is occurring due to an autocatalytic reaction, likely via the formation of mixed adsorbed species containing Fe and W compounds or nucleation clusters containing both metals on the electrode surface.
Feasibility Study of an Iron-Based Composite Added with Al2O3/ZrO2 as an Oxygen Carrier in the Chemical Looping Applications
Authors: Kao Ching-Ti , Shen Cheng-Hsien , Hsu Heng-Wen
Published: August 2021

The chemical looping process is a promising approach for carbon capture. Oxygen carriers play the crucial role of carrying oxygen between oxidation and reduction reactors. In this study, iron-based composites, added with alumina and zirconia, were used as the oxygen carriers. The feasibility study of these composites for chemical looping applications was then evaluated by measuring their properties, including mechanical properties, relative density, microstructures, crystal structure, and their capacity of oxygen. The results suggest that the addition of zirconia led the decrease of the bulk relative density and thus had a negative effect to both crush strength and attrition. Crush strength declined from 57 kgf to 26 kgf when using zirconia, replacing alumina, in an iron-based composite as the inner material. In addition, the phases in oxidizing and reducing reaction were also revealed. The formation of the spinel phase (FeAl2O4) was the major factor that altered the capacity of oxygen. It inhibited Fe2O3’s ability to be completely reduced to Fe and thus decrease the capacity of oxygen. The value was therefore decreased from 9.7% to 6.2% after 50 redox cycles in alumina addition composite. On the other hand, for the zirconia addition, all of the Fe2O3 could transform to Fe, which provided 8.5% of oxygen capacity after 50 redox cycles. A dense layer which was identified as the Fe2O3 in the bulk surface was observed in the samples reacted with 50 redox cycles. The proposed mechanism of the formation of Fe2O3 layer and its corresponding kinetic analysis was also revealed in this study.
Oxidation Behavior and Oxide Transformation of a Pt-Modified Aluminide Coating at Moderate High Temperature
Authors: Li Yanyan , Li Shuai , Zhang Chao , Xu Na , Bao Zebin
Published: August 2021

The oxidation performance of a single-phase Pt-modified aluminide coating was assessed in oxidation test at 980 °C in comparison with the single crystal superalloy. The results suggested that the Pt-modified aluminide coating exhibited superior oxidation resistance. During oxidation, the oxide scale formed on bare alloy changed constantly followed by the constitution of the multi-layer scale structure: An outer scale mainly consisted of Cr2O3 + NiCr2O4 + TiO2 with scarce protection, and an internal scale mainly consisted of Al2O3. The thickness of the outer oxide scale increased with time, where the scale became looser and more porous. Meanwhile, the internal scale was discontinuous. Oxygen and nitrogen inwardly diffused into substrate, forming Ta2O5 and TiN particles. In contrast to the complex constitution of oxide scale, a uniform and continuous Al2O3 scale formed on Pt-modified aluminide-coated samples after oxidation at 980 °C for 1500 h, which showed no spallation and cracking. Interestingly, θ-Al2O3 and α-Al2O3 phases remained after such a long oxidation time. It is the relatively lower temperature and the presence of Pt retarded θ-α transformation. The degradation rate from β-NiAl to γ′-Ni3Al was very slow in the coating. The various development of oxide scale on the coating and substrate was individually studied.
Transfer of a Rational Crystal Contact Engineering Strategy between Diverse Alcohol Dehydrogenases
Authors: Walla Brigitte , Bischoff Daniel , Janowski Robert , von den Eichen Nikolas , Niessing Dierk , Weuster-Botz Dirk
Published: August 2021

Protein crystallization can serve as a purification step in biotechnological processes but is often limited by the non-crystallizability of proteins. Enabling or improving crystallization is mostly achieved by high-throughput screening of crystallization conditions and, more recently, by rational crystal contact engineering. Two selected rational crystal contact mutations, Q126K and T102E, were transferred from the alcohol dehydrogenases of Lactobacillus brevis (LbADH) to Lactobacillus kefir (LkADH). Proteins were expressed in E. coli and batch protein crystallization was performed in stirred crystallizers. Highly similar crystal packing of LkADH wild type compared to LbADH, which is necessary for the transfer of crystal contact engineering strategies, was achieved by aligning purification tag and crystallization conditions, as shown by X-ray diffraction. After comparing the crystal sizes after crystallization of LkADH mutants with the wild type, the mean protein crystal size of LkADH mutants was reduced by 40–70% in length with a concomitant increase in the total amount of crystals (higher number of nucleation events). Applying this measure to the LkADH variants studied results in an order of crystallizability T102E > Q126K > LkADH wild type, which corresponds to the results with LbADH mutants and shows, for the first time, the successful transfer of crystal contact engineering strategies.