bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Hyaluronic Acid-Polylactic Acid/Silver Nanoparticles Core-Sheath Nanofiber Membranes for Prevention of Post-Operative Tendon Adhesion
Authors: Chen Chih-Hao , Cheng Yuan-Hsun , Chen Shih-Heng , Chuang Andy Deng-Chi , Chen Jyh-Ping
Published: August 2021

In this study, we prepared core-sheath nanofiber membranes (CSNFMs) with silver nanoparticles (Ag NPs) embedding in the polylactic acid (PLA) nanofiber sheath and hyaluronic acid (HA) in the nanofiber core. The PLA/Ag NPs sheath provides mechanical support as well as anti-bacterial and anti-inflammatory properties. The controlled release of HA from the core could exert anti-adhesion effects to promote tendon sliding while reducing fibroblast attachment. From the microfibrous structural nature of CSNFMs, they function as barrier membranes to reduce fibroblast penetration without hampering nutrient transports to prevent post-operative peritendinous adhesion. As the anti-adhesion efficacy will depend on release rate of HA from the core as well as Ag NP from the sheath, we fabricated CSNFMs of comparable fiber diameter, but with thick (Tk) or thin (Tn) sheath. Similar CSNFMs with thick (Tk+) and thin (Tn+) sheath but with embedded Ag NPs in the sheath were also prepared. The physico-chemical properties of the barrier membranes were characterized in details, together with their biological response including cell penetration, cell attachment and proliferation, and cytotoxicity. Peritendinous anti-adhesion models in rabbits were used to test the efficacy of CSNFMs as anti-adhesion barriers, from gross observation, histology, and biomechanical tests. Overall, the CSNFM with thin-sheath and Ag NPs (Tn+) shows antibacterial activity with low cytotoxicity, prevents fibroblast penetration, and exerts the highest efficacy in reducing fibroblast attachment in vitro. From in vivo studies, the Tn+ membrane also shows significant improvement in preventing peritendinous adhesions as well as anti-inflammatory efficacy, compared with Tk and Tn CSNFMs and a commercial adhesion barrier film (SurgiWrap®) made from PLA.
Anti-Cancer and Electrochemical Properties of Thiogenistein—New Biologically Active Compound
Authors: Stolarczyk Elżbieta U. , Strzempek Weronika , Łaszcz Marta , Leś Andrzej , Menaszek Elżbieta , Sidoryk Katarzyna , Stolarczyk Krzysztof
Published: August 2021

Pharmacological and nutraceutical effects of isoflavones, which include genistein (GE), are attributed to their antioxidant activity protecting cells against carcinogenesis. The knowledge of the oxidation mechanisms of an active substance is crucial to determine its pharmacological properties. The aim of the present work was to explain complex oxidation processes that have been simulated during voltammetric experiments for our new thiolated genistein analog (TGE) that formed the self-assembled monolayer (SAM) on the gold electrode. The thiol linker assured a strong interaction of sulfur nucleophiles with the gold surface. The research comprised of the study of TGE oxidative properties, IR-ATR, and MALDI-TOF measurements of SAM before and after electrochemical oxidation. TGE has been shown to be electrochemically active. It undergoes one irreversible oxidation reaction and one quasi-reversible oxidation reaction in PBS buffer at pH 7.4. The oxidation of TGE results in electroactive products composed likely from TGE conjugates (e.g., trimers) as part of polymer. The electroactive centers of TGE and its oxidation mechanism were discussed using IR supported by quantum chemical and molecular mechanics calculations. Preliminary in-vitro studies indicate that TGE exhibits higher cytotoxic activity towards DU145 human prostate cancer cells and is safer for normal prostate epithelial cells (PNT2) than genistein itself.
Gain-of-Function Mutant TP53 R248Q Overexpressed in Epithelial Ovarian Carcinoma Alters AKT-Dependent Regulation of Intercellular Trafficking in Responses to EGFR/MDM2 Inhibitor
Authors: Lai Zih-Yin , Tsai Kai-Yun , Chang Shing-Jyh , Chuang Yung-Jen
Published: August 2021

As the most common gene mutation found in cancers, p53 mutations are detected in up to 96% of high-grade serous ovarian carcinoma (HGSOC). Meanwhile, mutant p53 overexpression is known to drive oncogenic phenotypes in cancer patients and to sustain the activation of EGFR signaling. Previously, we have demonstrated that the combined inhibition of EGFR and MDM2-p53 pathways, by gefitinib and JNJ-26854165, exerts a strong synergistic lethal effect on HGSOC cells. In this study, we investigated whether the gain-of-function p53 mutation (p53R248Q) overexpression could affect EGFR-related signaling and the corresponding drug inhibition outcome in HGSOC. The targeted inhibition responses of gefitinib and JNJ-26854165, in p53R248Q-overexpressing cells, were extensively evaluated. We found that the phosphorylation of AKT increased when p53R248Q was transiently overexpressed. Immunocytochemistry analysis further showed that upon p53R248Q overexpression, several AKT-related regulatory proteins translocated in unique intracellular patterns. Subsequent analysis revealed that, under the combined inhibition of gefitinib and JNJ-26854165, the cytonuclear trafficking of EGFR and MDM2 was disrupted. Next, we analyzed the gefitinib and JNJ-26854165 responses and found differential sensitivity to the single- or combined-drug inhibitions in p53R248Q-overexpressing cells. Our findings suggested that the R248Q mutation of p53 in HGSOC caused significant changes in signaling protein function and trafficking, under EGFR/MDM2-targeted inhibition. Such knowledge could help to advance our understanding of the role of mutant p53 in ovarian carcinoma and to improve the prognosis of patients receiving EGFR/MDM2-targeted therapies.
Toxic and Teratogenic Effects of Prenatal Alcohol Exposure on Fetal Development, Adolescence, and Adulthood
Authors: Chung Dae D. , Pinson Marisa R. , Bhenderu Lokeshwar S. , Lai Michael S. , Patel Rhea A. , Miranda Rajesh C.
Published: August 2021

Prenatal alcohol exposure (PAE) can have immediate and long-lasting toxic and teratogenic effects on an individual’s development and health. As a toxicant, alcohol can lead to a variety of physical and neurological anomalies in the fetus that can lead to behavioral and other impairments which may last a lifetime. Recent studies have focused on identifying mechanisms that mediate the immediate teratogenic effects of alcohol on fetal development and mechanisms that facilitate the persistent toxic effects of alcohol on health and predisposition to disease later in life. This review focuses on the contribution of epigenetic modifications and intercellular transporters like extracellular vesicles to the toxicity of PAE and to immediate and long-term consequences on an individual’s health and risk of disease.
Direct Synthesis of Polyaromatic Cyclophanes Containing Bis-Methylene-Interrupted Z-Double Bonds and Study of Their Antitumor Activity In Vitro
Authors: D’yakonov Vladimir A. , Islamov Ilgiz I. , Dzhemileva Lilya U. , Makarova Elina Kh. , Dzhemilev Usein M.
Published: August 2021

An original synthetic route was developed for the preparation of previously unknown unsaturated polyaromatic macrolactones containing a 1Z,5Z-diene moiety in 48–71% yields and with >98% stereoselectivity. The method is based on intermolecular cyclocondensation of aromatic dicarboxylic acids with α,ω-alka-nZ,(n+4)Z-dienediols (1,12-dodeca-4Z,8Z-dienediol, 1,14-tetradeca-5Z,9Z-dienediol, 1,18-octadeca-7Z,11Z-dienediol) mediated by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)/4-dimethylaminopyridine (DMAP). The unsaturated diols were prepared by successive homo-cyclomagnesiation of tetrahydropyran ethers of O-containing 1,2-dienes with EtMgBr in the presence of Mg metal and the Cp2TiCl2 catalyst (10 mol.%) and subsequent treatment with 0.1 equiv. of para-toluenesulfonic acid of pyran ethers formed after the acid hydrolysis of magnesacyclopentanes. The resulting cyclophanes exhibited high cytotoxic activity in vitro against Jurkat, K562, U937, and HL60 cancer lines. Additionally, the synthesized products were studied for their effect on mitochondria, ability to induce apoptosis, and influence on the cell cycle using modern flow cytometry methods.
Previous Influenza Infection Exacerbates Allergen Specific Response and Impairs Airway Barrier Integrity in Pre-Sensitized Mice
Authors: Looi Kevin , Larcombe Alexander N. , Perks Kara L. , Berry Luke J. , Zosky Graeme R. , Rigby Paul , Knight Darryl A. , Kicic Anthony , Stick Stephen M.
Published: August 2021

In this study we assessed the effects of antigen exposure in mice pre-sensitized with allergen following viral infection on changes in lung function, cellular responses and tight junction expression. Female BALB/c mice were sensitized to ovalbumin and infected with influenza A before receiving a second ovalbumin sensitization and challenge with saline, ovalbumin (OVA) or house dust mite (HDM). Fifteen days post-infection, bronchoalveolar inflammation, serum antibodies, responsiveness to methacholine and barrier integrity were assessed. There was no effect of infection alone on bronchoalveolar lavage cellular inflammation 15 days post-infection; however, OVA or HDM challenge resulted in increased bronchoalveolar inflammation dominated by eosinophils/neutrophils or neutrophils, respectively. Previously infected mice had higher serum OVA-specific IgE compared with uninfected mice. Mice previously infected, sensitized and challenged with OVA were most responsive to methacholine with respect to airway resistance, while HDM challenge caused significant increases in both tissue damping and tissue elastance regardless of previous infection status. Previous influenza infection was associated with decreased claudin-1 expression in all groups and decreased occludin expression in OVA or HDM-challenged mice. This study demonstrates the importance of the respiratory epithelium in pre-sensitized individuals, where influenza-infection-induced barrier disruption resulted in increased systemic OVA sensitization and downstream effects on lung function.
Rosmarinic Acid Increases Macrophage Cholesterol Efflux through Regulation of ABCA1 and ABCG1 in Different Mechanisms
Authors: Nyandwi Jean-Baptiste , Ko Young Shin , Jin Hana , Yun Seung Pil , Park Sang Won , Kim Hye Jung
Published: August 2021

Lipid dysregulation in diabetes mellitus escalates endothelial dysfunction, the initial event in the development and progression of diabetic atherosclerosis. In addition, lipid-laden macrophage accumulation in the arterial wall plays a significant role in the pathology of diabetes-associated atherosclerosis. Therefore, inhibition of endothelial dysfunction and enhancement of macrophage cholesterol efflux is the important antiatherogenic mechanism. Rosmarinic acid (RA) possesses beneficial properties, including its anti-inflammatory, antioxidant, antidiabetic and cardioprotective effects. We previously reported that RA effectively inhibits diabetic endothelial dysfunction by inhibiting inflammasome activation in endothelial cells. However, its effect on cholesterol efflux remains unknown. Therefore, in this study, we aimed to assess the effect of RA on cholesterol efflux and its underlying mechanisms in macrophages. RA effectively reduced oxLDL-induced cholesterol contents under high glucose (HG) conditions in macrophages. RA enhanced ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) expression, promoting macrophage cholesterol efflux. Mechanistically, RA differentially regulated ABCA1 expression through JAK2/STAT3, JNK and PKC-p38 and ABCG1 expression through JAK2/STAT3, JNK and PKC-ERK1/2/p38 in macrophages. Moreover, RA primarily stabilized ABCA1 rather than ABCG1 protein levels by impairing protein degradation. These findings suggest RA as a candidate therapeutic to prevent atherosclerotic cardiovascular disease complications related to diabetes by regulating cholesterol efflux in macrophages.
Parallel Reporter Assays Identify Altered Regulatory Role of rs684232 in Leading to Prostate Cancer Predisposition
Authors: Ren Naixia , Liu Qingqing , Yan Lingjie , Huang Qilai
Published: August 2021

Functional characterization of cancer risk-associated single nucleotide polymorphism (SNP) identified by genome-wide association studies (GWAS) has become a big challenge. To identify the regulatory risk SNPs that can lead to transcriptional misregulation, we performed parallel reporter gene assays with both alleles of 213 prostate cancer risk-associated GWAS SNPs in 22Rv1 cells. We disclosed 32 regulatory SNPs that exhibited different regulatory activities with two alleles. For one of the regulatory SNPs, rs684232, we found that the variation altered chromatin binding of transcription factor FOXA1 on the DNA region and led to aberrant gene expression of VPS53, FAM57A, and GEMIN4, which play vital roles in prostate cancer malignancy. Our findings reveal the roles and underlying mechanism of rs684232 in prostate cancer progression and hold great promise in benefiting prostate cancer patients with prognostic prediction and target therapies.
Genome-Wide Identification and Expression Analysis of BBX Transcription Factors in Iris germanica L.
Authors: Wang Yinjie , Zhang Yongxia , Liu Qingquan , Zhang Ting , Chong Xinran , Yuan Haiyan
Published: August 2021

The family of B-box (BBX) transcription factors contains one or two B-BOX domains and sometimes also features a highly conserved CCT domain, which plays important roles in plant growth, development and stress response. Nevertheless, no systematic study of the BBX gene family in Iris germanica L. has been undertaken. In this study, a set of six BBX TF family genes from I. germanica was identified based on transcriptomic sequences, and clustered into three clades according to phylogenetic analysis. A transient expression analysis revealed that all six BBX proteins were localized in the nucleus. A yeast one-hybrid assay demonstrated that IgBBX3 has transactivational activity, while IgBBX1, IgBBX2, IgBBX4, and IgBBX5 have no transcriptional activation ability. The transcript abundance of IgBBXs in different tissues was divided into two major groups. The expression of IgBBX1, IgBBX2, IgBBX3 and IgBBX5 was higher in leaves, whereas IgBBX4 and IgBBX6 was higher in roots. The stress response patterns of six IgBBX were detected under phytohormone treatments and abiotic stresses. The results of this study lay the basis for further research on the functions of BBX gene family members in plant hormone and stress responses, which will promote their application in I. germanica breeding.
Coordinating DNA Replication and Mitosis through Ubiquitin/SUMO and CDK1
Authors: Galarreta Antonio , Valledor Pablo , Fernandez-Capetillo Oscar , Lecona Emilio
Published: August 2021

Post-translational modification of the DNA replication machinery by ubiquitin and SUMO plays key roles in the faithful duplication of the genetic information. Among other functions, ubiquitination and SUMOylation serve as signals for the extraction of factors from chromatin by the AAA ATPase VCP. In addition to the regulation of DNA replication initiation and elongation, we now know that ubiquitination mediates the disassembly of the replisome after DNA replication termination, a process that is essential to preserve genomic stability. Here, we review the recent evidence showing how active DNA replication restricts replisome ubiquitination to prevent the premature disassembly of the DNA replication machinery. Ubiquitination also mediates the removal of the replisome to allow DNA repair. Further, we discuss the interplay between ubiquitin-mediated replisome disassembly and the activation of CDK1 that is required to set up the transition from the S phase to mitosis. We propose the existence of a ubiquitin–CDK1 relay, where the disassembly of terminated replisomes increases CDK1 activity that, in turn, favors the ubiquitination and disassembly of more replisomes. This model has important implications for the mechanism of action of cancer therapies that induce the untimely activation of CDK1, thereby triggering premature replisome disassembly and DNA damage.
Organic Anion Transporting Polypeptide 1B1 Is a Potential Reporter for Dual MR and Optical Imaging
Authors: Lee Yi-Hsueh , Wu Menq-Rong , Hsiao Jong-Kai
Published: August 2021

Membrane proteins responsible for transporting magnetic resonance (MR) and fluorescent contrast agents are of particular importance because they are potential reporter proteins in noninvasive molecular imaging. Gadobenate dimeglumine (Gd-BOPTA), a liver-specific MR contrast agent, has been used globally for more than 10 years. However, the corresponding molecular transportation mechanism has not been validated. We previously reported that the organic anion transporting polypeptide (OATP) 1B3 has an uptake capability for both MR agents (Gd-EOB-DTPA) and indocyanine green (ICG), a clinically available near-infrared (NIR) fluorescent dye. This study further evaluated OATP1B1, another polypeptide of the OATP family, to determine its reporter capability. In the OATP1B1 transfected 293T transient expression model, both Gd-BOPTA and Gd-EOB-DTPA uptake were confirmed through 1.5 T MR imaging. In the constant OAPT1B1 and OATP1B3 expression model in the HT-1080 cell line, both HT-1080-OAPT1B1 and HT-1080-OATP1B3 were observed to ingest Gd-BOPTA and Gd-EOB-DTPA. Lastly, we validated the ICG uptake capability of both OATP1B1 and OATP1B3. OAPT1B3 exhibited a superior ICG uptake capability to that of OAPT1B1. We conclude that OATP1B1 is a potential reporter for dual MR and NIR fluorescent molecular imaging, especially in conjunction with Gd-BOPTA.
Exploring the Biological Activity and Mechanism of Xenoestrogens and Phytoestrogens in Cancers: Emerging Methods and Concepts
Authors: Wang Xiaoqiang , Ha Desiree , Yoshitake Ryohei , Chan Yin S. , Sadava David , Chen Shiuan
Published: August 2021

Xenoestrogens and phytoestrogens are referred to as “foreign estrogens” that are produced outside of the human body and have been shown to exert estrogen-like activity. Xenoestrogens are synthetic industrial chemicals, whereas phytoestrogens are chemicals present in the plant. Considering that these environmental estrogen mimics potentially promote hormone-related cancers, an understanding of how they interact with estrogenic pathways in human cells is crucial to resolve their possible impacts in cancer. Here, we conducted an extensive literature evaluation on the origins of these chemicals, emerging research techniques, updated molecular mechanisms, and ongoing clinical studies of estrogen mimics in human cancers. In this review, we describe new applications of patient-derived xenograft (PDX) models and single-cell RNA sequencing (scRNA-seq) techniques in shaping the current knowledge. At the molecular and cellular levels, we provide comprehensive and up-to-date insights into the mechanism of xenoestrogens and phytoestrogens in modulating the hallmarks of cancer. At the systemic level, we bring the emerging concept of window of susceptibility (WOS) into focus. WOS is the critical timing during the female lifespan that includes the prenatal, pubertal, pregnancy, and menopausal transition periods, during which the mammary glands are more sensitive to environmental exposures. Lastly, we reviewed 18 clinical trials on the application of phytoestrogens in the prevention or treatment of different cancers, conducted from 2002 to the present, and provide evidence-based perspectives on the clinical applications of phytoestrogens in cancers. Further research with carefully thought-through concepts and advanced methods on environmental estrogens will help to improve understanding for the identification of environmental influences, as well as provide novel mechanisms to guide the development of prevention and therapeutic approaches for human cancers.
Astrocytes Stimulate Microglial Proliferation and M2 Polarization In Vitro through Crosstalk between Astrocytes and Microglia
Authors: Kim Sumin , Son Youngsook
Published: August 2021

Microglia are resident immune cells of the central nervous system that act as brain-specific macrophages and are also known to regulate the innate immune functions of astrocytes through secretory molecules. This communication plays an important role in brain functions and homeostasis as well as in neuropathologic disease. In this study, we aimed to elucidate whether astrocytes and microglia could crosstalk to induce microglial polarization and proliferation, which can be further regulated under a microenvironment mimicking that of brain stroke. Microglia in a mixed glial culture showed increased survival and proliferation and were altered to M2 microglia; CD11b−GFAP+ astrocytes resulted in an approximately tenfold increase in microglial cell proliferation after the reconstitution of astrocytes. Furthermore, GM-CSF stimulated microglial proliferation approximately tenfold and induced them to become CCR7+ M1 microglia, which have a phenotype that could be suppressed by anti-inflammatory cytokines such as IL-4, IL-10, and substance P. In addition, the astrocytes in the microglial co-culture showed an A2 phenotype; they could be activated to A1 astrocytes by TNF-α and IFN-γ under the stroke-mimicking condition. Altogether, astrocytes in the mixed glial culture stimulated the proliferation of the microglia and M2 polarization, possibly through the acquisition of the A2 phenotype; both could be converted to M1 microglia and A1 astrocytes under the inflammatory stroke-mimicking environment. This study demonstrated that microglia and astrocytes could be polarized to M2 microglia and A2 astrocytes, respectively, through crosstalk in vitro and provides a system with which to explore how microglia and astrocytes may behave in the inflammatory disease milieu after in vivo transplantation.
MWNTs or PEG as Stability Enhancers for DNA–Cationic Surfactant Gel Particles
Authors: Mezei Amalia , Pons Ramon
Published: August 2021

Cationic surfactants interact with DNA (Deoxyribonucleic acid), forming surfactant-DNA complexes that offer particularly efficient control for encapsulation and release of DNA from DNA gel particles. In the present work, DNA-based particles were prepared using CTAB (Cetyltrimethylammonium bromide) as the cationic surfactant and modified using two different additives: (Multi-Walled Carbon Nanotubes) MWNT or PEG (Poly Ethylene Glycol). The use of both additives to form composites increased the stability of the gel particles. The stability was monitored by the release of DNA and CTAB in different pH solutions. However, not much is known about the influence of pH on DNA–surfactant interaction and the release of DNA and surfactant from gel particles. It was observed that the solubilization of DNA occurs only in very acid media, while that of CTAB does not depend on pH and gets to a plateau after about 8 h. Within 2 h in contact with a pH = 2 solution, about 1% DNA and CTAB was released. Complete destruction for the gel particles was observed in pH = 2 solution after 17 days for PEG and 20 days for MWNT. The composite particles show a considerably enlarged sustained release span compared to the unmodified ones. The dehydration-rehydration studies show that the structure of the composite gel particles, as determined from SAXS (Small-Angle-X-Ray-Scattering) experiments, is similar to that of the unmodified ones. These studies will allow a better knowledge of these particles’ formation and evolution in view of possible applications in drug delivery and release.
Pattern of TAAR5 Expression in the Human Brain Based on Transcriptome Datasets Analysis
Authors: Vaganova Anastasia N. , Murtazina Ramilya Z. , Shemyakova Taisiia S. , Prjibelski Andrey D. , Katolikova Nataliia V. , Gainetdinov Raul R.
Published: August 2021

Trace amine-associated receptors (TAAR) recognize organic compounds, including primary, secondary, and tertiary amines. The TAAR5 receptor is known to be involved in the olfactory sensing of innate socially relevant odors encoded by volatile amines. However, emerging data point to the involvement of TAAR5 in brain functions, particularly in the emotional behaviors mediated by the limbic system which suggests its potential contribution to the pathogenesis of neuropsychiatric diseases. TAAR5 expression was explored in datasets available in the Gene Expression Omnibus, Allen Brain Atlas, and Human Protein Atlas databases. Transcriptomic data demonstrate ubiquitous low TAAR5 expression in the cortical and limbic brain areas, the amygdala and the hippocampus, the nucleus accumbens, the thalamus, the hypothalamus, the basal ganglia, the cerebellum, the substantia nigra, and the white matter. Altered TAAR5 expression is identified in Down syndrome, major depressive disorder, or HIV-associated encephalitis. Taken together, these data indicate that TAAR5 in humans is expressed not only in the olfactory system but also in certain brain structures, including the limbic regions receiving olfactory input and involved in critical brain functions. Thus, TAAR5 can potentially be involved in the pathogenesis of brain disorders and represents a valuable novel target for neuropsychopharmacology.
Quantification of the Immune Content in Neuroblastoma: Deep Learning and Topological Data Analysis in Digital Pathology
Authors: Bussola Nicole , Papa Bruno , Melaiu Ombretta , Castellano Aurora , Fruci Doriana , Jurman Giuseppe
Published: August 2021

We introduce here a novel machine learning (ML) framework to address the issue of the quantitative assessment of the immune content in neuroblastoma (NB) specimens. First, the EUNet, a U-Net with an EfficientNet encoder, is trained to detect lymphocytes on tissue digital slides stained with the CD3 T-cell marker. The training set consists of 3782 images extracted from an original collection of 54 whole slide images (WSIs), manually annotated for a total of 73,751 lymphocytes. Resampling strategies, data augmentation, and transfer learning approaches are adopted to warrant reproducibility and to reduce the risk of overfitting and selection bias. Topological data analysis (TDA) is then used to define activation maps from different layers of the neural network at different stages of the training process, described by persistence diagrams (PD) and Betti curves. TDA is further integrated with the uniform manifold approximation and projection (UMAP) dimensionality reduction and the hierarchical density-based spatial clustering of applications with noise (HDBSCAN) algorithm for clustering, by the deep features, the relevant subgroups and structures, across different levels of the neural network. Finally, the recent TwoNN approach is leveraged to study the variation of the intrinsic dimensionality of the U-Net model. As the main task, the proposed pipeline is employed to evaluate the density of lymphocytes over the whole tissue area of the WSIs. The model achieves good results with mean absolute error 3.1 on test set, showing significant agreement between densities estimated by our EUNet model and by trained pathologists, thus indicating the potentialities of a promising new strategy in the quantification of the immune content in NB specimens. Moreover, the UMAP algorithm unveiled interesting patterns compatible with pathological characteristics, also highlighting novel insights into the dynamics of the intrinsic dataset dimensionality at different stages of the training process. All the experiments were run on the Microsoft Azure cloud platform.
Hearing Impairment in a Mouse Model of Diabetes Is Associated with Mitochondrial Dysfunction, Synaptopathy, and Activation of the Intrinsic Apoptosis Pathway
Authors: Lyu Ah-Ra , Kim Tae-Hwan , Shin Sun-Ae , Kim Eung-Hyub , Yu Yang , Gajbhiye Akanksha , Kwon Hyuk-Chan , Je A Reum , Huh Yang Hoon , Park Min Jung , Park Yong-Ho
Published: August 2021

Although previous studies continuously report an increased risk of hearing loss in diabetes patients, the impact of the disease on the inner ear remains unexplored. Herein, we examine the pathophysiology of diabetes-associated hearing impairment and cochlear synaptopathy in a mouse model of diabetes. Male B6.BKS(D)-Leprdb/J (db/db, diabetes) and heterozygote (db/+, control) mice were assigned into each experimental group (control vs. diabetes) based on the genotype and tested for hearing sensitivity every week from 6 weeks of age. Each cochlea was collected for histological and biological assays at 14 weeks of age. The diabetic mice exerted impaired hearing and a reduction in cochlear blood flow and C-terminal-binding protein 2 (CtBP2, a presynaptic ribbon marker) expression. Ultrastructural images revealed severely damaged mitochondria from diabetic cochlea accompanied by a reduction in Cytochrome c oxidase subunit 4 (COX4) and CR6-interacting factor 1 (CRIF1). The diabetic mice presented significantly decreased levels of platelet endothelial cell adhesion molecule (PECAM-1), B-cell lymphoma 2 (BCL-2), and procaspase-9, but not procaspase-8. Importantly, significant changes were not found in necroptotic programmed cell death markers (receptor-interacting serine/threonine-protein kinase 1, RIPK1; RIPK3; and mixed lineage kinase domain-like pseudokinase, MLKL) between the groups. Taken together, diabetic hearing loss is accompanied by synaptopathy, microangiopathy, damage to the mitochondrial structure/function, and activation of the intrinsic apoptosis pathway. Our results imply that mitochondrial dysfunction is deeply involved in diabetic hearing loss, and further suggests the potential benefits of therapeutic strategies targeting mitochondria.
Betulin Sulfonamides as Carbonic Anhydrase Inhibitors and Anticancer Agents in Breast Cancer Cells
Authors: Güttler Antje , Eiselt Yvonne , Funtan Anne , Thiel Andreas , Petrenko Marina , Keßler Jacqueline , Thondorf Iris , Paschke Reinhard , Vordermark Dirk , Bache Matthias
Published: August 2021

Hypoxia-regulated protein carbonic anhydrase IX (CA IX) is up-regulated in different tumor entities and correlated with poor prognosis in breast cancer patients. Due to the radio- and chemotherapy resistance of solid hypoxic tumors, derivatives of betulinic acid (BA), a natural compound with anticancer properties, seem to be promising to benefit these cancer patients. We synthesized new betulin sulfonamides and determined their cytotoxicity in different breast cancer cell lines. Additionally, we investigated their effects on clonogenic survival, cell death, extracellular pH, HIF-1α, CA IX and CA XII protein levels and radiosensitivity. Our study revealed that cytotoxicity increased after treatment with the betulin sulfonamides compared to BA or their precursors, especially in triple-negative breast cancer (TNBC) cells. CA IX activity as well as CA IX and CA XII protein levels were reduced by the betulin sulfonamides. We observed elevated inhibitory efficiency against protumorigenic processes such as proliferation and clonogenic survival and the promotion of cell death and radiosensitivity compared to the precursor derivatives. In particular, TNBC cells showed benefit from the addition of sulfonamides onto BA and revealed that betulin sulfonamides are promising compounds to treat more aggressive breast cancers, or are at the same level against less aggressive breast cancer cells.
The Impact of Physical Exercise on the Circulating Levels of BDNF and NT 4/5: A Review
Authors: Ribeiro Daniel , Petrigna Luca , Pereira Frederico C. , Muscella Antonella , Bianco Antonino , Tavares Paula
Published: August 2021

(1) Background: One mechanism through which physical activity (PA) provides benefits is by triggering activity at a molecular level, where neurotrophins (NTs) are known to play an important role. However, the expression of the circulating levels of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4/5), in response to exercise, is not fully understood. Therefore, the aim was to provide an updated overview on the neurotrophin (NT) variation levels of BDNF and NT-4/5 as a consequence of a long-term aerobic exercise intervention, and to understand and describe whether the upregulation of circulating NT levels is a result of neurotrophic factors produced and released from the brain, and/or from neurotrophic secreting peripheral organs. (2) Methods: The articles were collected from PubMed, SPORTDiscus, Web of Science, MEDLINE, and Embase. Data were analyzed through a narrative synthesis. (3) Results: 30 articles studied humans who performed training protocols that ranged from 4 to 48 weeks; 22 articles studied rodents with an intervention period that ranged from 4 to 64 weeks. (4) Conclusions: There is no unanimity between the upregulation of BDNF in humans; conversely, concerning both BDNF and NT-4/5 in animal models, the results are heterogeneous. Whilst BDNF upregulation appears to be in relative agreement, NT-4/5 seems to display contradictory and inconsistent conclusions.
Stimuli-Responsive Poly(aspartamide) Derivatives and Their Applications as Drug Carriers
Authors: Zhang Guangyan , Yi Hui , Bao Chenhui
Published: August 2021

Poly(aspartamide) derivatives, one kind of amino acid-based polymers with excellent biocompatibility and biodegradability, meet the key requirements for application in various areas of biomedicine. Poly(aspartamide) derivatives with stimuli-responsiveness can usually respond to external stimuli to change their chemical or physical properties. Using external stimuli such as temperature and pH as switches, these smart poly(aspartamide) derivatives can be used for convenient drug loading and controlled release. Here, we review the synthesis strategies for preparing these stimuli-responsive poly(aspartamide) derivatives and the latest developments in their applications as drug carriers.
Metabolic Comorbidities in Vitiligo: A Brief Review and Report of New Data from a Single-Center Experience
Authors: D’Arino Andrea , Picardo Mauro , Truglio Mauro , Pacifico Alessia , Iacovelli Paolo
Published: August 2021

Among disorders of pigmentation, vitiligo is the most common, with an estimated prevalence between 0.5% and 1%. The disease has gathered increased attention in the most recent years, leading to a better understanding of the disease’s pathophysiology and its implications and to the development of newer therapeutic strategies. A better, more integrated approach is already in use for other chronic inflammatory dermatological diseases such as psoriasis, for which metabolic comorbidities are well-established and part of the routine clinical evaluation. The pathogenesis of these might be linked to cytokines which also play a role in vitiligo pathogenesis, such as IL-1, IL-6, TNF-α, and possibly IL-17. Following the reports of intrinsic metabolic alterations reported by our group, in this brief review, we analyze the available data on metabolic comorbidities in vitiligo, accompanied by our single-center experience. Increased awareness of the metabolic aspects of vitiligo is crucial to improving patient care.
Development of a Rapid Fluorescent Diagnostic System to Detect Subtype H9 Influenza A Virus in Chicken Feces
Authors: Tuong Hien Thi , Jeong Ju Hwan , Choi Young Ki , Park Hyun , Baek Yun Hee , Yeo Seon-Ju
Published: August 2021

The circulation of the H9N2 virus results in significant economic losses in the poultry industry, and its zoonotic transmission highlights the need for a highly sensitive and rapid diagnostic and detection system for this virus. In this study, the performance of lateral flow test strips for a fluorescent immunochromatographic test (FICT) was optimized for the diagnosis of H9N2 virus-infected animal samples. The novel monoclonal antibodies (McAbs) against influenza A H9 viruses were developed, and two categories of McAbs with linear and conformational epitopes were compared for the performance of rapid diagnostic performance in the presence of feces sample at different time points (2, 4, and 6 days) post-infection (dpi). The limit of detection (LOD) of FICT and Kd values were comparable between linear and conformational epitope McAbs. However, superior performance of linear epitope McAbs pairs were confirmed by two animal studies, showing the better diagnostic performance showing 100% relative sensitivity in fecal samples at 6 dpi although it showed less than 80% sensitivity in early infection. Our results imply that the comparable performance of the linear epitope McAbs can potentially improve the diagnostic performance of FICT for H9N2 detection in feces samples. This highly sensitive rapid diagnostic method can be utilized in field studies of broiler poultry and wild birds.
Spatio–Environmental Analysis of Vespula germanica Nest Records Explains Slow Invasion in South Africa
Authors: Veldtman Ruan , Daly Derek , Bekker Gerard F. H. v. G.
Published: August 2021

Investigating the distributions of invasive species in marginal habitats can give clues to the factors constraining invasive spread. Vespula germanica is the most widely distributed of all the invasive Vespids, which in the Southern Hemisphere typically have large extensive invasive populations. In contrast, the invasion into South Africa has been slow and is still confined to a small geographic area. Here we analyse the distribution of all recent nest records in South Africa (n = 405). The distance to main rivers, mean annual rainfall, summer normalised difference moisture index (NDMI) values, and mean annual temperatures (average, minimum, maximum, and summer maximum temperature) was measured for every nest. We find that value ranges of these variables are different between the value ranges recorded for nests, the general distribution area of the wasp, and the area of absence. Optimised Hot Spot Analysis was used to quantify spatial structure in the measured climatic variables. Generally, factors related to moisture stress set the environmental limits of V. germanica’s landscape distribution. Due to the strong preference of nesting sites close to river courses, for higher rainfall conditions, medium to medium-high NDMI values, and lower mean annual temperatures, it is unlikely that V. germanica will be able to spread uniformly where it is currently found in South Africa.
Extracorporeal Shockwave Therapy (ESWT) Alleviates Pain, Enhances Erectile Function and Improves Quality of Life in Patients with Chronic Prostatitis/Chronic Pelvic Pain Syndrome
Authors: Wu Wen-Ling , Bamodu Oluwaseun Adebayo , Wang Yuan-Hung , Hu Su-Wei , Tzou Kai-Yi , Yeh Chi-Tai , Wu Chia-Chang
Published: August 2021

Purpose: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), affecting over 90% of patients with symptomatic prostatitis, remains a therapeutic challenge and adversely affects patients’ quality of life (QoL). This study probed for likely beneficial effects of ESWT, evaluating its extent and durability. Patients and methods: Standardized indices, namely the pain, urinary, and QoL domains and total score of NIH-CPSI, IIEF-5, EHS, IPSS, and AUA QoL_US were employed in this study of patients with CP/CPPS who had been refractory to other prior treatments (n = 215; age range: 32–82 years; median age: 57.5 ± 12.4 years; modal age: 41 years). Results: For CP symptoms, the mean pre-ESWT NIH-CPSI total score of 27.1 ± 6.8 decreased by 31.3–53.6% over 12 months after ESWT. The mean pre-ESWT NIH-CPSI pain (12.5 ± 3.3), urinary (4.98 ± 2.7), and QoL (9.62 ± 2.1) domain scores improved by 2.3-fold, 2.2-fold, and 2.0-fold, respectively, by month 12 post-ESWT. Compared with the baseline IPSS of 13.9 ± 8.41, we recorded 27.1–50.9% amelioration of urinary symptoms during the 12 months post-ESWT. For erectile function, compared to pre-ESWT values, the IIEF-5 also improved by ~1.3-fold by month 12 after ESWT. This was corroborated by EHS of 3.11 ± 0.99, 3.37 ± 0.65, 3.42 ± 0.58, 3.75 ± 0.45, and 3.32 ± 0.85 at baseline, 1, 2, 6, and 12 months post-ESWT. Compared to the mean pre-ESWT QoL score (4.29 ± 1.54), the mean QoL values were 3.26 ± 1.93, 3.45 ± 2.34, 3.25 ± 1.69, and 2.6 ± 1.56 for months 1, 2, 6, and 12 after ESWT, respectively. Conclusions: This study shows ESWT, an outpatient and easy-to-perform, minimally invasive procedure, effectively alleviates pain, improves erectile function, and ameliorates quality of life in patients with refractory CP/CPPS.
Association among Autistic Traits, Treatment Intensity and Outcomes in Adolescents with Anorexia Nervosa: Preliminary Results
Authors: Pruccoli Jacopo , Rosa Simone , Cesaroni Carlo Alberto , Malaspina Elisabetta , Parmeggiani Antonia
Published: August 2021

The present study investigates the impact of Autism Spectrum Disorder (ASD) traits on the treatment intensity and outcomes (psychopathology and weight) of 22 adolescent inpatients with Anorexia Nervosa (AN), who were selected on the basis of suspected ASD traits. ASD traits were measured at admission (T0) using the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) and the Autism-Spectrum Quotient (AQ). Psychopathology was measured with Eating Disorder Inventory-3 (EDI-3) and Self-Administered Psychiatric Scales for Children and Adolescents (SAFA) at admission and discharge (T0, T1). Percentage BMI was assessed at admission, discharge, first follow-up (T2, 7–22 days) and second follow-up (T3, 22–45 days). Results were controlled for age and EDI-3 global psychological maladjustment. When compared with other patients with AN, AN individuals with ADOS-2 and AQ diagnostic scores for ASD showed overlapping types of treatments, as well as psychopathological and weight outcomes. ASD total scores were not correlated with treatment intensity or treatment outcomes. Preliminary results show that ASD traits do not impact treatment intensity and outcomes in adolescents with AN and suspected ASD traits.
Assessment of Electrosensitivity of the Pulp of the Mandibular Second Molar after Surgical Removal of an Impacted Mandibular Third Molar
Authors: Trybek Grzegorz , Aniko-Włodarczyk Magda , Preuss Olga , Jaroń Aleksandra
Published: August 2021

Despite the frequent discussion of complications associated with surgical removal of wisdom teeth in the scientific literature, increased mobility of the second molar, which can affect the clinical status of the pulp, is often downplayed or overlooked. This study aimed to evaluate surgical removal of an impacted third molar on the change in the electrosensitivity of the pulp of the mandibular second molar. Sixty patients consecutively presenting to the Department of Oral Surgery to remove an impacted mandibular third molar were included in the study. Clinical examinations of pulp sensitivity of second molars in both the study and control groups were evaluated before the procedure, seven days after the procedure, and eight weeks after the procedure. The surgical removal of an impacted mandibular third molar significantly affected the pulp sensitivity of the second molar.
Thyroid Hormones—An Underestimated Player in Dilated Cardiomyopathy?
Authors: Zawadzka Karolina , Dziedzic Radosław , Surdacki Andrzej , Chyrchel Bernadeta
Published: August 2021

Dilated cardiomyopathy (DCM) is the most prevalent cardiomyopathy, typified by left ventricular dilation and systolic dysfunction. Many patients with DCM have altered thyroid status, especially lower levels of free triiodothyronine (T3) and elevated levels of thyroid-stimulating hormone. Moreover, growing evidence indicates that even subtle changes in thyroid status (especially low T3) are linked with a worse long-term prognosis and a higher risk of mortality. Notably, recent discoveries have shown that not only local myocardial thyroid hormones (THs) bioavailability could be diminished due to impaired expression of the activating deiodinase, but virtually all genes involved in TH biosynthesis are also expressed in the myocardium of DCM patients. Importantly, some studies have suggested beneficial effects of TH therapy in patients suffering from DCM. Our aim was to discuss new insights into the association between TH status and prognosis in DCM, abnormal expression of genes involved in the myocardial synthesis of TH in DCM, and the potential for TH use in the future treatment of DCM.
Shunt Overdrainage: Reappraisal of the Syndrome and Proposal for an Integrative Model
Authors: Ros Bienvenido , Iglesias Sara , Linares Jorge , Cerro Laura , Casado Julia , Arráez Miguel Angel
Published: August 2021

Although shunt overdrainage is a well-known complication in hydrocephalus management, the problem has been underestimated. Current literature suggests that the topic requires more examination. An insight into this condition is limited by a lack of universally agreed-upon diagnostic criteria, heterogeneity of published series, the multitude of different management options and misunderstanding of relationships among pathophysiological mechanisms involved. We carried out a review of the literature on clinical, radiological, intracranial pressure (ICP), pathophysiological and treatment concepts to finally propose an integrative model. Active prophylaxis and management are proposed according to this model based on determination of pathophysiological mechanisms and predisposing factors behind each individual case. As pathophysiology is progressively multifactorial, prevention of siphoning with gravitational valves or antisiphon devices is mandatory to avoid or minimize further complications. Shunt optimization or transferal and neuroendoscopy may be recommended when ventricular collapse and cerebrospinal fluid isolation appear. Cranial expansion may be useful in congenital or acquired craniocerebral disproportion and shunting the subarachnoid space in communicating venous hydrocephalus and idiopathic intracranial hypertension.
Green Synthesis of Gold, Silver, and Iron Nanoparticles for the Degradation of Organic Pollutants in Wastewater
Authors: Kumar Brajesh
Published: August 2021

The green synthesis of nanoscale materials is of special interest to researchers all over the world. We describe a simple, robust, inexpensive, and environmentally friendly approach to the synthesis of gold, silver, and iron nanoparticles using a variety of biomolecules/phytochemicals as potential reducers and stabilizers. The green approach to the controlled synthesis of nanoparticles with different morphologies is based on the use of plant extracts. Green synthesized nanoparticles can be used as catalysts, photocatalysts, adsorbents, or alternative agents for the elimination of various organic dyes. The kinetic enhancement of nanoparticles for the degradation/removal of dyes could provide significant and valuable insights for the application of biochemically functionalized nanoparticles in engineering. In this review, current plant-mediated strategies for preparing nanoparticles of gold, silver, and iron are briefly described, and morphologically dependent nanoparticles for the degradation of organic pollutants in wastewater are highlighted. Overall, the approach presented in the article supports environmental protection and is a promising alternative to other synthesis techniques.