bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization and Use in Wheat Breeding of Leaf Rust Resistance Genes from Durable Varieties
Authors: Diéguez María José , López Micaela , Altieri Emiliano , Pergolesi María Fernanda , Dabove Marisol Alicia , Cuyeu Alba Romina , Justus Nadia , Kandus Mariana , Ingala Lorena , Sacco Francisco
Published: November 2021

Leaf rust is one of the most significant diseases of wheat worldwide. In Argentina, it is one of the main reasons for variety replacement that becomes susceptible after large-scale use. Some varieties showed durable resistance to this disease, including Buck Manantial and Sinvalocho MA. RILs (Recombinant Inbred Lines) were developed for each of these varieties and used in genetics studies to identify components of resistance, both in greenhouse inoculations using leaf rust races, and in field evaluations under natural population infections. In Buck Manantial, the APR gene LrBMP1 was associated with resistance in field tests. In crosses involving Sinvalocho MA, four genes were previously identified and associated with resistance in field testing: APR (Adult Plant Resistance) gene LrSV1, the APR genetic system LrSV2 + LrcSV2 and the ASR (All Stage Resistance) gene LrG6. Using backcrosses, LrBMP1 was introgressed in four commercial susceptible varieties and LrSV1, LrSV2 + LrcSV2 and LrG6 were simultaneously introgressed in three susceptible commercial varieties. The use of molecular markers for recurrent parent background selection allowed us to select resistant lines with more than 80% similarity to commercial varieties. Additionally, progress towards positional cloning of the genetic system LrSV2 + LrcSV2 for leaf rust APR is reported.
Multi-Target In Silico Prediction of Inhibitors for Mitogen-Activated Protein Kinase-Interacting Kinases
Authors: Halder Amit Kumar , Cordeiro M. Natália D. S.
Published: November 2021

The inhibitors of two isoforms of mitogen-activated protein kinase-interacting kinases (i.e., MNK-1 and MNK-2) are implicated in the treatment of a number of diseases including cancer. This work reports, for the first time, a multi-target (or multi-tasking) in silico modeling approach (mt-QSAR) for probing the inhibitory potential of these isoforms against MNKs. Linear and non-linear mt-QSAR classification models were set up from a large dataset of 1892 chemicals tested under a variety of assay conditions, based on the Box–Jenkins moving average approach, along with a range of feature selection algorithms and machine learning tools, out of which the most predictive one (>90% overall accuracy) was used for mechanistic interpretation of the likely inhibition of MNK-1 and MNK-2. Considering that the latter model is suitable for virtual screening of chemical libraries—i.e., commercial, non-commercial and in-house sets, it was made publicly accessible as a ready-to-use FLASK-based application. Additionally, this work employed a focused kinase library for virtual screening using an mt-QSAR model. The virtual hits identified in this process were further filtered by using a similarity search, in silico prediction of drug-likeness, and ADME profiles as well as synthetic accessibility tools. Finally, molecular dynamic simulations were carried out to identify and select the most promising virtual hits. The information gathered from this work can supply important guidelines for the discovery of novel MNK-1/2 inhibitors as potential therapeutic agents.
Changes in the Expression of Renal Brush Border Membrane N-Glycome in Model Rats with Chronic Kidney Diseases
Authors: Yu Aiying , Zhao Jingfu , Yadav Shiv Pratap S. , Molitoris Bruce A. , Wagner Mark C. , Mechref Yehia
Published: November 2021

Chronic kidney disease (CKD) is defined by a reduced renal function i.e., glomerular filtration rate (GFR), and the presence of kidney damage is determined by measurement of proteinuria or albuminuria. Albuminuria increases with age and can result from glomerular and/or proximal tubule (PT) alterations. Brush-border membranes (BBMs) on PT cells play an important role in maintaining the stability of PT functions. The PT BBM, a highly dynamic, organized, specialized membrane, contains a variety of glycoproteins required for the functions of PT. Since protein glycosylation regulates many protein functions, the alteration of glycosylation due to the glycan changes has attracted more interests for a variety of disease studies recently. In this work, liquid chromatography-tandem mass spectrometry was utilized to analyze the abundances of permethylated glycans from rats under control to mild CKD, severe CKD, and diabetic conditions. The most significant differences were observed in sialylation level with the highest present in the severe CKD and diabetic groups. Moreover, high mannose N-glycans was enriched in the CKD BBMs. Characterization of all the BBM N-glycan changes supports that these changes are likely to impact the functional properties of the dynamic PT BBM. Further, these changes may lead to the potential discovery of glycan biomarkers for improved CKD diagnosis and new avenues for therapeutic treatments.
Overwinter Changes in the Lipid Profile of Young-of-the-Year Striped Bass (Morone saxatilis) in Freshwater Ponds
Authors: Tonning Kare A. , Budge Suzanne M. , Tyedmers Peter
Published: November 2021

Young-of-the-year (YOY) striped bass (Morone saxatilis) suffer significant mortality during their first winter. While causes of this mortality are unclear, lipids may play role in adapting to winter stresses, including thermal change and food scarcity. To address this, YOY striped bass were placed in mesh cages in freshwater ponds in the fall (November) and were held until the end of winter, in March. Liver and white muscle tissue were sampled at the beginning and end of the study to compare concentrations of specific lipid classes and fatty acid composition. Muscle-tissue total lipid and triacylglycerol (TAG) was higher in March (late winter) samples. Additionally, concentrations of phosphatidylethanolamine (PE) were higher in the white muscle of striped bass sampled in March; this was accompanied by a decrease in proportions of 18:0 and 22:6n-3 in PE (from ~11 to 7% and 36 to 28%, respectively) and 18:1n-9 and 22:6n-3 in phosphatidylcholine (from ~15 to 10% and 24 to 18%, respectively). This suggests that these fish were not utilizing energy reserves in previously described ways and appear to rely more on other lipid classes or body tissues for overwinter survival than those analyzed in this study.
Changes in Cardiac Metabolism in Prediabetes
Authors: de Wit-Verheggen Vera H. W. , van de Weijer Tineke
Published: November 2021

In type 2 diabetes mellitus (T2DM), there is an increased prevalence of cardiovascular disease (CVD), even when corrected for atherosclerosis and other CVD risk factors. Diastolic dysfunction is one of the early changes in cardiac function that precedes the onset of cardiac failure, and it occurs already in the prediabetic state. It is clear that these changes are closely linked to alterations in cardiac metabolism; however, the exact etiology is unknown. In this narrative review, we provide an overview of the early cardiac changes in fatty acid and glucose metabolism in prediabetes and its consequences on cardiac function. A better understanding of the relationship between metabolism, mitochondrial function, and cardiac function will lead to insights into the etiology of the declined cardiac function in prediabetes.
Cellulose–Silver Composites Materials: Preparation and Applications
Authors: Salama Ahmed , Abouzeid Ragab E. , Owda Medhat E. , Cruz-Maya Iriczalli , Guarino Vincenzo
Published: November 2021

Cellulose has received great attention owing to its distinctive structural features, exciting physico−chemical properties, and varied applications. The combination of cellulose and silver nanoparticles currently allows to fabricate different promising functional nanocomposites with unique properties. The current work offers a wide and accurate overview of the preparation methods of cellulose–silver nanocomposite materials, also providing a punctual discussion of their potential applications in different fields (i.e., wound dressing, high-performance textiles, electronics, catalysis, sensing, antimicrobial filtering, and packaging). In particular, different preparation methods of cellulose/silver nanocomposites based on in situ thermal reduction, blending and dip-coating, or additive manufacturing techniques were thoroughly described. Hence, the correlations among the structure and physico–chemical properties in cellulose/silver nanocomposites were investigated in order to better control the final properties of the nanocomposites and analyze the key points and limitations of the current manufacturing approaches.
Role of Ferroptosis in Non-Alcoholic Fatty Liver Disease and Its Implications for Therapeutic Strategies
Authors: Zhang Han , Zhang Enxiang , Hu Hongbo
Published: November 2021

Non-alcoholic fatty liver disease (NAFLD) has become the chronic liver disease with the highest incidence throughout the world, but its pathogenesis has not been fully elucidated. Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation. Abnormal iron metabolism, lipid peroxidation, and accumulation of polyunsaturated fatty acid phospholipids (PUFA-PLs) can all trigger ferroptosis. Emerging evidence indicates that ferroptosis plays a critical role in the pathological progression of NAFLD. Because the liver is the main organ for iron storage and lipid metabolism, ferroptosis is an ideal target for liver diseases. Inhibiting ferroptosis may become a new therapeutic strategy for the treatment of NAFLD. In this article, we describe the role of ferroptosis in the progression of NAFLD and its related mechanisms. This review will highlight further directions for the treatment of NAFLD and the selection of corresponding drugs that target ferroptosis.
miRNAs and lncRNAs: Potential Non-Invasive Biomarkers for Endometriosis
Authors: Maier Ioana Maria , Maier Adrian Cornel
Published: November 2021

Many studies have tried to understand the mechanism of endometriosis and its manner of manifestation. However, the only method of diagnosis considered as the gold standard in endometriosis is an invasive method called exploratory laparoscopy. Hence, there is a need to identify non-invasive or minimally invasive methods to minimize patients’ suffering, thus increasing their addressability at the earliest possible staging of the disease, and to diagnose this condition as soon as possible. miRNAs (microRNAs) and lncRNAs (long-noncoding RNAs) are potential non-invasive diagnostic methods for endometriosis. Multiple clinical trials indicate that miRNA can be used as a non-invasive method in the diagnosis and differentiation of endometriosis stages.
Mitochondria-Mediated Apoptosis of HCC Cells Triggered by Knockdown of Glutamate Dehydrogenase 1: Perspective for Its Inhibition through Quercetin and Permethylated Anigopreissin A
Authors: Marsico Michela , Santarsiero Anna , Pappalardo Ilaria , Convertini Paolo , Chiummiento Lucia , Sardone Alessandra , Di Noia Maria Antonietta , Infantino Vittoria , Todisco Simona
Published: November 2021

Metabolic reprogramming is a hallmark of cancer cells required to ensure high energy needs and the maintenance of redox balance. A relevant metabolic change of cancer cell bioenergetics is the increase in glutamine metabolism. Hepatocellular carcinoma (HCC), one of the most lethal cancer and which requires the continuous development of new therapeutic strategies, shows an up-regulation of human glutamate dehydrogenase 1 (hGDH1). GDH1 function may be relevant in cancer cells (or HCC) to drive the glutamine catabolism from L-glutamate towards the synthesis of α-ketoglutarate (α-KG), thus supplying key tricarboxylic acid cycle (TCA cycle) metabolites. Here, the effects of hGLUD1 gene silencing (siGLUD1) and GDH1 inhibition were evaluated. Our results demonstrate that siGLUD1 in HepG2 cells induces a significant reduction in cell proliferation (58.8% ± 10.63%), a decrease in BCL2 expression levels, mitochondrial mass (75% ± 5.89%), mitochondrial membrane potential (30% ± 7.06%), and a significant increase in mitochondrial superoxide anion (25% ± 6.55%) compared to control/untreated cells. The inhibition strategy leads us to identify two possible inhibitors of hGDH1: quercetin and Permethylated Anigopreissin A (PAA). These findings suggest that hGDH1 could be a potential candidate target to impair the metabolic reprogramming of HCC cells.
Vitamin-Containing Antioxidant Formulation Reduces Carcinogen-Induced DNA Damage through ATR/Chk1 Signaling in Bronchial Epithelial Cells In Vitro
Authors: Merlin J.P. Jose , Dellaire Graham , Murphy Kieran , Rupasinghe H.P. Vasantha
Published: November 2021

Lung cancer has the highest mortality rate worldwide and is often diagnosed at late stages, requiring genotoxic chemotherapy with significant side effects. Cancer prevention has become a major focus, including the use of dietary and supplemental antioxidants. Thus, we investigated the ability of an antioxidant formulation (AOX1) to reduce DNA damage in human bronchial epithelial cells (BEAS-2B) with and without the combination of apple peel flavonoid fraction (AF4), or its major constituent quercetin (Q), or Q-3-O-d-glucoside (Q3G) in vitro. To model smoke-related genotoxicity, we used cigarette-smoke hydrocarbon 4-[(acetoxymethyl)nitrosamino]-1-(3-pyridyl)-1-butanone (NNKOAc) as well as methotrexate (MTX) to induce DNA damage in BEAS-2B cells. DNA fragmentation, γ-H2AX immunofluorescence, and comet assays were used as indicators of DNA damage. Pre-exposure to AOX1 alone or in combination with AF4, Q, or Q3G before challenging with NNKOAc and MTX significantly reduced intracellular reactive oxygen species (ROS) levels and DNA damage in BEAS-2B cells. Although NNKOAc-induced DNA damage activated ATM-Rad3-related (ATR) and Chk1 kinase in BEAS-2B cells, pre-exposure of the cells with tested antioxidants prior to carcinogen challenge significantly reduced their activation and levels of γ-H2AX (p ≤ 0.05). Therefore, AOX1 alone or combined with flavonoids holds promise as a chemoprotectant by reducing ROS and DNA damage to attenuate activation of ATR kinase following carcinogen exposure.
Methods of Modification of Mesenchymal Stem Cells and Conditions of Their Culturing for Hyaline Cartilage Tissue Engineering
Authors: Shestovskaya Maria V. , Bozhkova Svetlana A. , Sopova Julia V. , Khotin Mikhail G. , Bozhokin Mikhail S.
Published: November 2021

The use of mesenchymal stromal cells (MSCs) for tissue engineering of hyaline cartilage is a topical area of regenerative medicine that has already entered clinical practice. The key stage of this procedure is to create conditions for chondrogenic differentiation of MSCs, increase the synthesis of hyaline cartilage extracellular matrix proteins by these cells and activate their proliferation. The first such works consisted in the indirect modification of cells, namely, in changing the conditions in which they are located, including microfracturing of the subchondral bone and the use of 3D biodegradable scaffolds. The most effective methods for modifying the cell culture of MSCs are protein and physical, which have already been partially introduced into clinical practice. Genetic methods for modifying MSCs, despite their effectiveness, have significant limitations. Techniques have not yet been developed that allow studying the effectiveness of their application even in limited groups of patients. The use of MSC modification methods allows precise regulation of cell culture proliferation, and in combination with the use of a 3D biodegradable scaffold, it allows obtaining a hyaline-like regenerate in the damaged area. This review is devoted to the consideration and comparison of various methods used to modify the cell culture of MSCs for their use in regenerative medicine of cartilage tissue.
An Additively Manufactured Sample Holder to Measure the Controlled Release of Vancomycin from Collagen Laminates
Authors: Kilb Michelle Fiona , Moos Yannik , Eckes Stefanie , Braun Joy , Ritz Ulrike , Nickel Daniela , Schmitz Katja
Published: November 2021

The controlled release of antibiotics prevents the spread of pathogens and thereby improves healing processes in regenerative medicine. However, high concentrations may interfere with healing processes. It is therefore advantageous to use biodegradable materials for a controlled release. In particular, multilayer materials enable differential release at different surfaces. For this purpose, collagen sheets of different properties can be bonded by photochemical crosslinking. Here, we present the development and application of an easily accessible, additively manufactured sample holder to study the controlled release of vancomycin from modularly assembled collagen laminates in two directions. As proof-of-concept, we show that laminates of collagen sheets covalently linked by rose bengal and green light crosslinking (RGX) can be tightly inserted into the device without leakage from the upper to lower cavity. We used this sample holder to detect the release of vancomycin from symmetrically and asymmetrically loaded two-layer and three-layer collagen laminates into the upper and lower cavity of the sample holder. We show that these collagen laminates are characterized by a collagen type-dependent vancomycin release, enabling the control of antibiotic release profiles as well as the direction of antibiotic release.
Blood Compatibility of Amphiphilic Phosphorous Dendrons—Prospective Drug Nanocarriers
Authors: Suty Simon , Oravczova Veronika , Garaiova Zuzana , Subjakova Veronika , Ionov Maksim , Shcharbin Dzmitry , Simonikova Zuzana , Bartek Peter , Zvarik Milan , Shi Xiangyang , Mignani Serge , Majoral Jean-Pierre , Bryszewska Maria , Hianik Tibor , Waczulikova Iveta
Published: November 2021

Dendrons are branched synthetic polymers suitable for preparation of nanosized drug delivery systems. Their interactions with biological systems are mainly predetermined by their chemical structure, terminal groups, surface charge, and the number of branched layers (generation). Any new compound intended to be used, alone or in combination, for medical purposes in humans must be compatible with blood. This study combined results from in vitro experiments on human blood and from laboratory experiments designed to assess the effect of amphiphilic phosphorous dendrons on blood components and model membranes, and to examine the presence and nature of interactions leading to a potential safety concern. The changes in hematological and coagulation parameters upon the addition of dendrons in the concentration range of 2–10 µM were monitored. We found that only the combination of higher concentration and higher generation of the dendron affected the selected clinically relevant parameters: it significantly decreased platelet count and plateletcrit, shortened thrombin time, and increased activated partial thromboplastin time. At the same time, occasional small-sized platelet clumps in blood films under the light microscope were observed. We further investigated aggregation propensity of the positively charged dendrons in model conditions using zwitterionic and negatively charged liposomes. The observed changes in size and zeta potential indicated the electrostatic nature of the interaction. Overall, we proved that the low-generation amphiphilic phosphorous dendrons were compatible with blood within the studied concentration range. However, interactions between high-generation dendrons at bulk concentrations above 10 µM and platelets and/or clotting factors cannot be excluded.
Recent Advances in Multicellular Tumor Spheroid Generation for Drug Screening
Authors: Lee Kwang-Ho , Kim Tae-Hyung
Published: November 2021

Multicellular tumor spheroids (MCTs) have been employed in biomedical fields owing to their advantage in designing a three-dimensional (3D) solid tumor model. For controlling multicellular cancer spheroids, mimicking the tumor extracellular matrix (ECM) microenvironment is important to understand cell–cell and cell–matrix interactions. In drug cytotoxicity assessments, MCTs provide better mimicry of conventional solid tumors that can precisely represent anticancer drug candidates’ effects. To generate incubate multicellular spheroids, researchers have developed several 3D multicellular spheroid culture technologies to establish a research background and a platform using tumor modelingvia advanced materials science, and biosensing techniques for drug-screening. In application, drug screening was performed in both invasive and non-invasive manners, according to their impact on the spheroids. Here, we review the trend of 3D spheroid culture technology and culture platforms, and their combination with various biosensing techniques for drug screening in the biomedical field.
Relationships between Freezing of Gait Severity and Cognitive Deficits in Parkinson’s Disease
Authors: Scholl Jamie L. , Espinoza Arturo I. , Rai Wijdan , Leedom Matt , Baugh Lee A. , Berg-Poppe Patti , Singh Arun
Published: November 2021

Freezing of gait (FOG) is one of the most debilitating motor symptoms experienced by patients with Parkinson’s disease (PD), as it can lead to falls and a reduced quality of life. Evidence supports an association between FOG severity and cognitive functioning; however, results remain debatable. PD patients with (PDFOG+, n = 41) and without FOG (PDFOG–, n = 39) and control healthy subjects (n = 41) participated in this study. The NIH toolbox cognition battery, the Montreal Cognitive Assessment (MoCA), and the interval timing task were used to test cognitive domains. Measurements were compared between groups using multivariable models and adjusting for covariates. Correlation analyses, linear regression, and mediation models were applied to examine relationships among disease duration and severity, FOG severity, and cognitive functioning. Significant differences were observed between controls and PD patients for all cognitive domains. PDFOG+ and PDFOG– exhibited differences in Dimensional Change Card Sort (DCCS) test, interval timing task, and MoCA scores. After adjusting for covariates in two different models, PDFOG+ and PDFOG– differed in both MoCA and DCCS scores. In addition, significant relationships between FOG severity and cognitive function (MoCA, DCCS, and interval timing) were also found. Regression models suggest that FOG severity may be a predictor of cognitive impairment, and mediation models show the effects of cognitive impairment on the relationship between disease severity and FOG severity. Overall, this study provides insight into the relationship between cognitive and FOG severity in patients with PD, which could aid in the development of therapeutic interventions to manage both.
Classification of Factors Effect on Sleep in Individuals with Down Syndrome
Authors: Nguyen Thai Duy , Baillieul Sébastien , Guinot Michel , Doutreleau Stéphane , Bricout Véronique-Aurélie
Published: November 2021

Background: Sleep disordered breathing (SDB) is a frequent disorder with serious adverse health consequences in people with Down syndrome (DS). This study aims to evaluate and classify sleep and physical activity (PA) characteristics in adults with DS. Methods: Forty participants with DS wore an accelerometer for seven consecutive days to measure physical activity and sleep–wake patterns. The corresponding data were also obtained by survey and polysomnography. The apnea-hypopnea index (AHI) is calculated from the number of apneas and hypopneas per hour of sleep according to international guidelines. Results: Polysomnography showed SDB based on AHI in 95% of adults: 50% had severe SDB, 22.5% presented moderate and 22.5% mild SDB, predominantly in males. They had poor sleep quality (80.1%) and low PA levels. Using statistical classification methods, we observed three clusters with two opposite profiles. Clusters 2 and 3 showed low PA indices (daily steps: 5719 and 5310, respectively) and severe SDB (AHI = 33.6 and 55.5 events/h), high age and high gonial angle. Cluster 1 showed high PA (mean count of daily steps: 6908) and mild to moderate SDB (AHI = 16.8 events/h), low age and low gonial angle. Conclusions: Our findings suggest that there are different profiles (age, gender, obesity, gonial angle) that are associated with SDB in adults with DS. These results suggest that this may represent important factors to consider when planning health promotion and prevention.
Graphene Synthesis and Its Recent Advances in Applications—A Review
Authors: Santhiran Anuluxan , Iyngaran Poobalasuntharam , Abiman Poobalasingam , Kuganathan Navaratnarajah
Published: November 2021

Owing to the remarkable chemical and physical properties, graphene has been widely investigated by researchers over the last 15 years. This review summarizes major synthetic methods such as mechanical exfoliation, liquid phase exfoliation, unzipping of carbon nanotube, oxidation-reduction, arc discharge, chemical vapor deposition, and epitaxial growth of graphene in silicon carbide. Recent advances in the application of graphene in graphene-based lithium ion batteries, supercapacitors, electrochemical sensors, transparent electrodes and environmental based remedies are discussed.
Siblings with MAN1B1-CDG Showing Novel Biochemical Profiles
Authors: Okamoto Nobuhiko , Ohto Tatsuyuki , Enokizono Takashi , Wada Yoshinao , Kohmoto Tomohiro , Imoto Issei , Haga Yoshimi , Seino Junichi , Suzuki Tadashi
Published: November 2021

Congenital disorders of glycosylation (CDG), inherited metabolic diseases caused by defects in glycosylation, are characterized by a high frequency of intellectual disability (ID) and various clinical manifestations. Two siblings with ID, dysmorphic features, and epilepsy were examined using mass spectrometry of serum transferrin, which revealed a CDG type 2 pattern. Whole-exome sequencing showed that both patients were homozygous for a novel pathogenic variant of MAN1B1 (NM_016219.4:c.1837del) inherited from their healthy parents. We conducted a HPLC analysis of sialylated N-linked glycans released from total plasma proteins and characterized the α1,2-mannosidase I activity of the lymphocyte microsome fraction. The accumulation of monosialoglycans was observed in MAN1B1-deficient patients, indicating N-glycan-processing defects. The enzymatic activity of MAN1B1 was compromised in patient-derived lymphocytes. The present patients exhibited unique manifestations including early-onset epileptic encephalopathy and cerebral infarction. They also showed coagulation abnormalities and hypertransaminasemia. Neither sibling had truncal obesity, which is one of the characteristic features of MAN1B1-CDG.
Reciprocal Regulation of Hippo and WBP2 Signalling—Implications in Cancer Therapy
Authors: Lim Yvonne Xinyi , Lin Hexian , Seah Sock Hong , Lim Yoon Pin
Published: November 2021

Cancer is a global health problem. The delineation of molecular mechanisms pertinent to cancer initiation and development has spurred cancer therapy in the form of precision medicine. The Hippo signalling pathway is a tumour suppressor pathway implicated in a multitude of cancers. Elucidation of the Hippo pathway has revealed an increasing number of regulators that are implicated, some being potential therapeutic targets for cancer interventions. WW domain-binding protein 2 (WBP2) is an oncogenic transcriptional co-factor that interacts, amongst others, with two other transcriptional co-activators, YAP and TAZ, in the Hippo pathway. WBP2 was recently discovered to modulate the upstream Hippo signalling components by associating with LATS2 and WWC3. Exacerbating the complexity of the WBP2/Hippo network, WBP2 itself is reciprocally regulated by Hippo-mediated microRNA biogenesis, contributing to a positive feedback loop that further drives carcinogenesis. Here, we summarise the biological mechanisms of WBP2/Hippo reciprocal regulation and propose therapeutic strategies to overcome Hippo defects in cancers through targeting WBP2.
Hedgehog Pathway Inhibitors against Tumor Microenvironment
Authors: Gampala Silpa , Yang Jer-Yen
Published: November 2021

Targeting the hedgehog (HH) pathway to treat aggressive cancers of the brain, breast, pancreas, and prostate has been ongoing for decades. Gli gene amplifications have been long discovered within malignant glioma patients, and since then, inhibitors against HH pathway-associated molecules have successfully reached the clinical stage where several of them have been approved by the FDA. Albeit this success rate implies suitable progress, clinically used HH pathway inhibitors fail to treat patients with metastatic or recurrent disease. This is mainly due to heterogeneous tumor cells that have acquired resistance to the inhibitors along with the obstacle of effectively targeting the tumor microenvironment (TME). Severe side effects such as hyponatremia, diarrhea, fatigue, amenorrhea, nausea, hair loss, abnormal taste, and weight loss have also been reported. Furthermore, HH signaling is known to be involved in the regulation of immune cell maturation, angiogenesis, inflammation, and polarization of macrophages and myeloid-derived suppressor cells. It is critical to determine key mechanisms that can be targeted at different levels of tumor development and progression to address various clinical issues. Hence current research focus encompasses understanding how HH controls TME to develop TME altering and combinatorial targeting strategies. In this review, we aim to discuss the pros and cons of targeting HH signaling molecules, understand the mechanism involved in treatment resistance, reveal the role of the HH pathway in anti-tumor immune response, and explore the development of potential combination treatment of immune checkpoint inhibitors with HH pathway inhibitors to target HH-driven cancers.
Regulation of PXR Function by Coactivator and Corepressor Proteins: Ligand Binding Is Just the Beginning
Authors: Rigalli Juan Pablo , Theile Dirk , Nilles Julie , Weiss Johanna
Published: November 2021

The pregnane X receptor (PXR, NR1I2) is a nuclear receptor which exerts its regulatory function by heterodimerization with the retinoid-X-receptor α (RXRα, NR2B1) and binding to the promoter and enhancer regions of diverse target genes. PXR is involved in the regulation of drug metabolism and excretion, metabolic and immunological functions and cancer pathogenesis. PXR activity is strongly regulated by the association with coactivator and corepressor proteins. Coactivator proteins exhibit histone acetyltransferase or histone methyltransferase activity or associate with proteins having one of these activities, thus promoting chromatin decondensation and activation of the gene expression. On the contrary, corepressor proteins promote histone deacetylation and therefore favor chromatin condensation and repression of the gene expression. Several studies pointed to clear cell- and ligand-specific differences in the activation of PXR. In this article, we will review the critical role of coactivator and corepressor proteins as molecular determinants of the specificity of PXR-mediated effects. As already known for other nuclear receptors, understanding the complex mechanism of PXR activation in each cell type and under particular physiological and pathophysiological conditions may lead to the development of selective modulators with therapeutic potential.
A Unique Topoisomerase II Inhibitor with Dose-Affected Anticancer Mechanisms and Less Cardiotoxicity
Authors: Li Zhi-Ying , Xu Guang-Sen , Li Xun
Published: November 2021

Type II DNA topoisomerase (topo II) is an essential nuclear enzyme and a well-validated anticancer drug target. Previously, we have carried out several rounds of structural optimizations on our in-house topo II inhibitor E17, which was shown to have superior anticancer activity and less risk of multidrug resistance (MDR). Among the newly developed acridone derivatives, 6h displayed significant anticancer efficacy with unique mechanisms of action. At low concentrations, it arrested cancer cell cycles and triggered cell apoptosis, which is similar to the action of the well-known topo II inhibitor VP16. By contrast, 6h showed significant and long-term anti-proliferative activity at relatively high concentrations, with negligible influence on apoptosis. In addition, 6h exhibited no serious cardiotoxicity compared to doxorubicin (DOXO), a widely used topo II-targeting antineoplastic drug in clinic, but with damaging myocardial side effects. Collectively, our present work has supported the therapeutic value of 6h as a promising chemotherapy for cancers.
Failure Analysis of TEVG’s I: Overcoming the Initial Stages of Blood Material Interaction and Stabilization of the Immune Response
Authors: Rodriguez-Soto Maria A. , Suarez Vargas Natalia , Riveros Alejandra , Camargo Carolina Muñoz , Cruz Juan C. , Sandoval Nestor , Briceño Juan C.
Published: November 2021

Vascular grafts (VG) are medical devices intended to replace the function of a diseased vessel. Current approaches use non-biodegradable materials that struggle to maintain patency under complex hemodynamic conditions. Even with the current advances in tissue engineering and regenerative medicine with the tissue engineered vascular grafts (TEVGs), the cellular response is not yet close to mimicking the biological function of native vessels, and the understanding of the interactions between cells from the blood and the vascular wall with the material in operative conditions is much needed. These interactions change over time after the implantation of the graft. Here we aim to analyze the current knowledge in bio-molecular interactions between blood components, cells and materials that lead either to an early failure or to the stabilization of the vascular graft before the wall regeneration begins.
Autophagy in α-Synucleinopathies—An Overstrained System
Authors: Fellner Lisa , Gabassi Elisa , Haybaeck Johannes , Edenhofer Frank
Published: November 2021

Alpha-synucleinopathies comprise progressive neurodegenerative diseases, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). They all exhibit the same pathological hallmark, which is the formation of α-synuclein positive deposits in neuronal or glial cells. The aggregation of α-synuclein in the cell body of neurons, giving rise to the so-called Lewy bodies (LBs), is the major characteristic for PD and DLB, whereas the accumulation of α-synuclein in oligodendroglial cells, so-called glial cytoplasmic inclusions (GCIs), is the hallmark for MSA. The mechanisms involved in the intracytoplasmic inclusion formation in neuronal and oligodendroglial cells are not fully understood to date. A possible mechanism could be an impaired autophagic machinery that cannot cope with the high intracellular amount of α-synuclein. In fact, different studies showed that reduced autophagy is involved in α-synuclein aggregation. Furthermore, altered levels of different autophagy markers were reported in PD, DLB, and MSA brains. To date, the trigger point in disease initiation is not entirely clear; that is, whether autophagy dysfunction alone suffices to increase α-synuclein or whether α-synuclein is the pathogenic driver. In the current review, we discuss the involvement of defective autophagy machinery in the formation of α-synuclein aggregates, propagation of α-synuclein, and the resulting neurodegenerative processes in α-synucleinopathies.
Trauma-Focused Tuning in to Kids: Evaluation in a Clinical Service
Authors: Havighurst Sophie , Murphy Jessica , Kehoe Christiane
Published: November 2021

This study evaluated the Tuning in to Kids (TIK) parenting program delivered in a clinical setting with 77 parents and caregivers (hereafter referred to as “parents”) of children who had experienced complex trauma. The TIK program targets parent emotion socialization to improve children’s emotional and behavioral functioning. The study utilized a single-group design with pre- and post-intervention measures. Seventy-seven parents of children (aged 3–15 years) who had experienced complex trauma completed a ten-week version of the Trauma-Focused Tuning in to Kids program (TF-TIK). Measures examined parent reports of: emotion socialization; parent-child relationship; parent mental health; children’s emotional and behavioral functioning. Parents reported significantly improved emotion socialization, parent-child relationship, parent mental health, as well as child emotion regulation and behavior. This study provides initial support for the use of the TF-TIK parenting program in a clinical setting with parents of children who have experienced complex trauma in order to prevent or reduce problems.
Improvement in Fine Manual Dexterity in Children with Spinal Muscular Atrophy Type 2 after Nusinersen Injection: A Case Series
Authors: Gu Minsu , Kong Hyun-Ho
Published: November 2021

Although nusinersen has been demonstrated to improve motor function in patients with spinal muscular atrophy (SMA), no studies have investigated its effect on fine manual dexterity. The present study aimed to investigate the ability of nusinersen to improve fine manual dexterity in patients with SMA type 2. A total of five patients with SMA type 2 were included. The Hammersmith Functional Motor Scale (expanded version) (HFMSE) and Purdue Pegboard (PP) tests were used to evaluate gross motor function and fine manual dexterity, respectively, until 18 months after nusinersen administration. HFMSE scores improved by 3–10 points (+13–53%) in all patients following nusinersen administration. PP scores also improved in all patients, from 4 to 9 points (+80–225%) in the preferred hand and from 3 to 7 points (+60–500%) in the non-preferred hand. These results suggest that nusinersen treatment improved both gross motor function and fine manual dexterity in children with SMA type 2. Addition of the PP test may aid in evaluating the fine manual dexterity essential for activities of daily living in these patients.
Muscle Ultrasonographic Elastography in Children: Review of the Current Knowledge and Application
Authors: Cebula Agnieszka , Cebula Maciej , Kopyta Ilona
Published: November 2021

Ultrasonographic elastography is a relatively new imaging modality for the qualitative and quantitative assessments of tissue elasticity. While it has steadily gained use in adult clinical practice, including for liver diseases, breast cancer, thyroid pathologies, and muscle and tendon diseases, data on its paediatric application is still limited. Moreover, diagnosis of muscular diseases in children remains challenging. The gold standard methods, namely biopsy, electroneurography, and electromyography, are often limited owing to their invasive characteristics, possible contraindications, complications, and need for good cooperation, that is, a patient’s ability to perform certain tasks during the examination while withstanding discomfort, which is a significant problem especially in younger or uncooperative children. Genetic testing, which has broad diagnostic possibilities, often entails a high cost, which limits its application. Thus, a non-invasive, objective, repeatable, and accessible tool is needed to aid in both the diagnosis and monitoring of muscle pathologies. We believe that elastography may prove to be such a method. The aim of this review was to present the current knowledge on the use of muscle elastography in the paediatric population and information on the limitations of elastography in relation to examination protocols and factors for consideration in everyday practice and future studies.
Effect of HfO2-Based Multi-Dielectrics on Electrical Properties of Amorphous In-Ga-Zn-O Thin Film Transistors
Authors: Wang Ruozheng , Wei Qiang , Li Jie , Fu Jiao , Liu Yiwei , Zhu Tianfei , Yu Cui , Niu Gang , Wu Shengli , Wang Hongxing
Published: November 2021

We report the fabrication of bottom gate a-IGZO TFTs based on HfO2 stacked dielectrics with decent electrical characteristics and bias stability. The microscopic, electrical, and optical properties of room temperature deposited a-IGZO film with varied oxygen content were explored. In order to suppress the bulk defects in the HfO2 thin film and hence maximize the quality, surface modification of the SiNx film was investigated so as to achieve a more uniform layer. The root mean square (RMS) roughness of SiNx/HfO2/SiNx (SHS) stacked dielectrics was only 0.66 nm, which was reduced by 35% compared with HfO2 single film (1.04 nm). The basic electrical characteristics of SHS-based a-IGZO TFT were as follows: Vth is 2.4 V, μsat is 21.1 cm2 V−1 s−1, Ion/Ioff of 3.3 × 107, Ioff is 10−11 A, and SS is 0.22 V/dec. Zr-doped HfO2 could form a more stable surface, which will decrease the bulk defect states so that the stability of device can be improved. It was found that the electrical characteristics were improved after Zr doping, with a Vth of 1.4 V, Ion/Ioff of 108, μsat of 19.5 cm2 V−1 s−1, Ioff of 10−12 A, SS of 0.18 V/dec. After positive gate bias stress of 104 s, the ΔVth was decreased from 0.43 V (without Zr doping) to 0.09 V (with Zr doping), the ΔSS was decreased from 0.19 V/dec to 0.057 V/dec, respectively, which shows a meaningful impact to realize the long-term working stability of TFT devices.
Clinical Application of Silver Nanoparticles Coated by Benzalkonium Chloride
Authors: Ansari Shakeel Ahmed , Alshanberi Asim Muhammed
Published: November 2021

The present study investigates the surface modification of AgNPs (synthesized by neem leaves) by benzalkonium chloride (BAC). It was observed that 22 × 109 CFU were formed at 0.25 mM AgNPs concentration. However, it was reduced to 14 × 109 CFU for BAC-coated AgNPs at similar experimental conditions. The enzymatic activity of β-glucosidase was significantly enhanced from 0.0625 mM to 0.5 mM concentration of AgNPs, as well as BAC–AgNPs. However, there was no further change of activity beyond this concentration. ZOI of AgNPs and BAC–AgNPs was measured against E. coli, B. subtilis, P. aeruginosa, and S pneumoniae at 0.25 mM and 0.50 mM concentrations of these bioactive agents. ZOI was 3.45 cm and 3.56 cm for AgNPs and BAC–AgNPs at 0.25 mM of these bioactive agents, respectively, against E. coli. However, these values were 4.28 cm and 4.40 cm, respectively, against B. subtilis. ZOI was obtained at 3.36 cm and 3.47 cm, respectively, against P. aeruginosa under similar experimental concentrations. However, ZOI was achieved at 3.44 cm and 3.62 cm, respectively, against S. pneumonia, under similar experimental conditions. Hence, such research findings can be exploited for potential applications in numerous environmental and biomedical fields.
Functionality of Films from Nigella sativa Defatted Seed Cake Proteins Plasticized with Grape Juice: Use in Wrapping Sweet Cherries
Authors: Yaseen Dana , Sabbah Mohammed , Al-Asmar Asmaa , Altamimi Mohammad , Famiglietti Michela , Giosafatto C. Valeria L. , Mariniello Loredana
Published: November 2021

The main aim of this work is to improve the functionality of Nigella sativa protein concentrate (NSPC) films by using grape juice (GJ). The film’s mechanical, antioxidant, and antimicrobial activities were evaluated. The obtained results showed, for the first time, that GJ at concentrations of 2%–10% (v/v) are able to act as plasticizer for the NSPC films with promising film properties. The results showed that the tensile strength and Young’s modulus of NSPC films were reduced significantly when the GJ increased. However, the NSPC films prepared with 6% GJ observed a higher elongation at break compared with other films. Moreover, the obtained films showed very interesting and promising results for their antioxidant and antimicrobial properties compared with the control films. The sweet cherries wrapped with NSPC film showed that the TSS (Brix) was significantly lower compared to the control, after 10 days of storage. However, the titratable acidity, pH value, and L* of all cherries, either wrapped or not, was not significantly different in all storage times. On the other hand, hue angle was significantly lower after 10 days of storage at −18 °C compared with control films. GJ has a multi-functional effect for protein-based films as plasticizer, antioxidant, and antimicrobial function.
Multiscale Convergence of the Inverse Problem for Chemotaxis in the Bayesian Setting
Authors: Hellmuth Kathrin , Klingenberg Christian , Li Qin , Tang Min
Published: November 2021

Chemotaxis describes the movement of an organism, such as single or multi-cellular organisms and bacteria, in response to a chemical stimulus. Two widely used models to describe the phenomenon are the celebrated Keller–Segel equation and a chemotaxis kinetic equation. These two equations describe the organism’s movement at the macro- and mesoscopic level, respectively, and are asymptotically equivalent in the parabolic regime. The way in which the organism responds to a chemical stimulus is embedded in the diffusion/advection coefficients of the Keller–Segel equation or the turning kernel of the chemotaxis kinetic equation. Experiments are conducted to measure the time dynamics of the organisms’ population level movement when reacting to certain stimulation. From this, one infers the chemotaxis response, which constitutes an inverse problem. In this paper, we discuss the relation between both the macro- and mesoscopic inverse problems, each of which is associated with two different forward models. The discussion is presented in the Bayesian framework, where the posterior distribution of the turning kernel of the organism population is sought. We prove the asymptotic equivalence of the two posterior distributions.
The Influence of Supercooling and Hydrodynamics on the Mosaic and Radial Inhomogeneity of K2NiXCo(1–X)(SO4)2·6H2O Mixed Crystal
Authors: Vasilyeva Natalia A. , Rudneva Elena B. , Manomenova Vera L. , Grigoriev Yuriy V. , Voloshin Alexey E.
Published: November 2021

The mosaic and radial inhomogeneity of shaped mixed crystals of K2NixCo(1–x)(SO4)2·6H2O (KCNSH) were studied depending on the supercooling of solution, its velocity and its method of supply into the shaper. It was shown that mosaic inhomogeneity could be suppressed when solution is supercooled to about 2 °C. Peripheral supply of the solution (tangential to the wall of the shaper to create a “swirling” flow) with a rate of 55–135 cm/s provides better composition uniformity along the crystal surface in comparison with upright supply of the solution (flow is perpendicular to the crystal surface).
Inverse Fiber Reinforced Polymer/Metal-Hybrid Laminates for Structural Lightweight Applications
Authors: Osiecki Tomasz , Timmel Tristan , Jałbrzykowski Marek , Przekop Robert E. , Oksiuta Zbigniew
Published: November 2021

Composite multi-material structures for the automotive industry are another step forward. This is because they contribute to a significant reduction in the weight of structural elements, and thus to energy savings and, consequently, lower emissivity of toxic gases. The paper presents research on a new multi-material system made of fiber-reinforced thermoplastics (FRP) combined with metal elements. To improve the adhesion between the metal insert and the fiber-reinforced plastic, an innovative combination of mechanical fit and adhesive was used. As a result, a targeted use of the excellent mechanical properties of the proposed structure was achieved. Additionally, the proposed method shows advantages in mass production processes of mass-optimized products with high stiffness and load-bearing capacity. The paper presents the results of a new material bending test.