bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the Influence of Urban Morphology on Urban Wind Environment Based on Computational Fluid Dynamics Simulation
Authors: Ku Chia-An , Tsai Hung-Kai
Published: June 2020

Due to urbanization around the world, people living in urban areas have been suffering from a series of negative effects caused by changes in urban microclimate, especially when it comes to urban heat islands (UHIs). To mitigate UHIs, management of urban wind environments is increasingly considered as a crucial part of the process. Computational fluid dynamics (CFD) simulation of wind fields has become a prevailing method to explore the relationship between morphological factors and wind environment. However, most studies are focused on building scale and fail to reflect the effects of comprehensive planning. In addition, the combined influence of different morphological factors on wind environment is rarely discussed. Therefore, this study tries to explore the relationship between urban morphology and wind environment in a new-town area. CFD method was applied to simulate the wind field, and 11 scenarios based on criteria according to existing literature, planning regulations and local characteristics were developed. The simulation results from different scenarios show that the impact of the five selected factors on wind speeds was non-linear, and the impact varied significantly among different areas of the study region. Simulation of the differences in regional wind speeds among different planning scenarios can provide strong decision-making support.
Synthesis of New Star-Shaped Liquid Crystalline Cyclotriphosphazene Derivatives with Fire Retardancy Bearing Amide-Azo and Azo-Azo Linking Units
Authors: Jamain Zuhair , Khairuddean Melati , Guan-Seng Tay
Published: June 2020

Two series of new hexasubstituted cyclotriphosphazene derivatives were successfully synthesized and characterized. These derivatives are differentiated by two types of linking units in the molecules such as amide-azo (6a–j) and azo-azo (8a–j). The homologues of the same series contain different terminal substituents such as heptyl, nonyl, decyl, dodecyl, tetradecyl, hydroxyl, carboxyl, chloro, nitro, and amino groups. All the intermediates and final compounds were characterized using Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance spectroscopy (NMR), and Carbon, Hydrogen, and Nitrogen (CHN) elemental analysis. Liquid crystal properties for all compounds were determined using polarized optical microscope (POM). It was found that only intermediates 2a–e with nitro and alkoxyl terminal chains showed a smectic A phase. All the final compounds with alkoxyl substituents are mesogenic with either smectic A or C phases. However, other intermediates and compounds were found to be non-mesogenic. The study on the fire retardancy of final compounds was determined using limiting oxygen index (LOI) method. The LOI value of pure polyester resin (22.53%) was increased up to 24.71% after treating with 1 wt% of hexachlorocyclotriphosphazene (HCCP). Moreover, all the compounds gave positive results on the LOI values and compound 6i with the nitro terminal substituent showed the highest LOI value of 27.54%.
EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration
Authors: Shu Daisy Y. , Butcher Erik , Saint-Geniez Magali
Published: June 2020

Epithelial–mesenchymal transition (EMT) and endothelial–mesenchymal transition (EndMT) are physiological processes required for normal embryogenesis. However, these processes can be hijacked in pathological conditions to facilitate tissue fibrosis and cancer metastasis. In the eye, EMT and EndMT play key roles in the pathogenesis of subretinal fibrosis, the end-stage of age-related macular degeneration (AMD) that leads to profound and permanent vision loss. Predominant in subretinal fibrotic lesions are matrix-producing mesenchymal cells believed to originate from the retinal pigment epithelium (RPE) and/or choroidal endothelial cells (CECs) through EMT and EndMT, respectively. Recent evidence suggests that EMT of RPE may also be implicated during the early stages of AMD. Transforming growth factor-beta (TGFβ) is a key cytokine orchestrating both EMT and EndMT. Investigations in the molecular mechanisms underpinning EMT and EndMT in AMD have implicated a myriad of contributing factors including signaling pathways, extracellular matrix remodelling, oxidative stress, inflammation, autophagy, metabolism and mitochondrial dysfunction. Questions arise as to differences in the mesenchymal cells derived from these two processes and their distinct mechanistic contributions to the pathogenesis of AMD. Detailed discussion on the AMD microenvironment highlights the synergistic interactions between RPE and CECs that may augment the EMT and EndMT processes in vivo. Understanding the differential regulatory networks of EMT and EndMT and their contributions to both the dry and wet forms of AMD can aid the development of therapeutic strategies targeting both RPE and CECs to potentially reverse the aberrant cellular transdifferentiation processes, regenerate the retina and thus restore vision.
Wnt Signaling in Gynecologic Malignancies
Authors: McMellen Alexandra , Woodruff Elizabeth R. , Corr Bradley R. , Bitler Benjamin G. , Moroney Marisa R.
Published: June 2020

Gynecologic malignancies, including ovarian cancer, endometrial cancer, and cervical cancer, affect hundreds of thousands of women worldwide every year. Wnt signaling, specifically Wnt/β-catenin signaling, has been found to play an essential role in many oncogenic processes in gynecologic malignancies, including tumorigenesis, metastasis, recurrence, and chemotherapy resistance. As such, the Wnt/β-catenin signaling pathway has the potential to be a target for effective treatment, improving patient outcomes. In this review, we discuss the evidence supporting the importance of the Wnt signaling pathways in the development, progression, and treatment of gynecologic malignancies.
Neuronal Reprogramming for Tissue Repair and Neuroregeneration
Authors: Liou Roxanne Hsiang-Chi , Edwards Thomas L. , Martin Keith R. , Wong Raymond Ching-Bong
Published: June 2020

Stem cell and cell reprogramming technology represent a rapidly growing field in regenerative medicine. A number of novel neural reprogramming methods have been established, using pluripotent stem cells (PSCs) or direct reprogramming, to efficiently derive specific neuronal cell types for therapeutic applications. Both in vitro and in vivo cellular reprogramming provide diverse therapeutic pathways for modeling neurological diseases and injury repair. In particular, the retina has emerged as a promising target for clinical application of regenerative medicine. Herein, we review the potential of neuronal reprogramming to develop regenerative strategy, with a particular focus on treating retinal degenerative diseases and discuss future directions and challenges in the field.
Therapeutic Potential of Tauroursodeoxycholic Acid for the Treatment of Osteoporosis
Authors: Ahn Tae-Keun , Kim Kyoung-Tae , Joshi Hari Prasad , Park Kwang Hwan , Kyung Jae Won , Choi Un-Yong , Sohn Seil , Sheen Seung-Hun , Shin Dong-Eun , Lee Soo-Hong , Han In-Bo
Published: June 2020

Tauroursodeoxycholic acid (TUDCA) is a US FDA-approved hydrophilic bile acid for the treatment of chronic cholestatic liver disease. In the present study, we investigate the effects of TUDCA on the proliferation and differentiation of osteoblasts and its therapeutic effect on a mice model of osteoporosis. Following treatment with different concentrations of TUDCA, cell viability, differentiation, and mineralization were measured. Three-month-old female C57BL/6 mice were randomly divided into three groups (n = 8 mice per group): (i) normal mice as the control group, (ii) ovariectomy (OVX) group (receiving phosphate-buffered saline (PBS) treatment every other day for 4 weeks), and (iii) OVX group with TUDCA (receiving TUDCA treatment every other day for 4 weeks starting 6 weeks after OVX). At 11 weeks post-surgery, serum levels of procollagen type I N-terminal propeptides (PINP) and type I collagen crosslinked C-telopeptides (CTX) were measured, and all mice were sacrificed to examine the distal femur by micro-computed tomography (CT) scans and histology. TUDCA (100 nM, 1 µM) significantly increased the proliferation and viability of osteoblasts and osteoblast differentiation and mineralization when used in vitro. Furthermore, TUDCA neutralized the detrimental effects of methylprednisolone (methylprednisolone-induced osteoblast apoptosis). In the TUDCA treatment group the PINP level was higher and the CTX level was lower, but these levels were not significantly different compared to the PBS treatment group. Micro-CT and histology showed that the TUDCA treatment group preserved more trabecular structures in the distal femur compared to the PBS treatment group. In addition, the TUDCA treatment group increased the percentage bone volume with respect to the total bone volume, bone mineral density, and mice distal femur trabeculae compared with the PBS treatment group. Taken together, our findings suggest that TUDCA may provide a favorable effect on bones and could be used for the prevention and treatment of osteoporosis.
Effect of Berberine on Glycation, Aldose Reductase Activity, and Oxidative Stress in the Lenses of Streptozotocin-Induced Diabetic Rats In Vivo—A Preliminary Study
Authors: Zych Maria , Wojnar Weronika , Kielanowska Magdalena , Folwarczna Joanna , Kaczmarczyk-Sedlak Ilona
Published: June 2020

Diabetes mellitus affects the eye lens, leading to cataract formation by glycation, osmotic stress, and oxidative stress. Berberine, an isoquinoline alkaloid, is a natural compound that has been reported to counteract all these pathological processes in various tissues and organs. The goal of this study was to evaluate whether berberine administered at a dose of 50 mg/kg by oral gavage for 28 days to rats with streptozotocin-induced diabetes reveals such effects on the biochemical parameters in the lenses. For this purpose, the following lenticular parameters were studied: concentrations of soluble protein, non-protein sulfhydryl groups (NPSH), advanced oxidation protein products (AOPP), advanced glycation end-products (AGEs), thiobarbituric acid reactive substances (TBARS), and activities of aldose reductase (AR), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Diabetes induced unfavorable changes in the majority of the examined parameters. The administration of berberine resulted in an increased soluble protein level, decreased activity of AR, and lowered AOPP and AGEs levels. The results suggest that berberine administered orally positively affects the lenses of diabetic rats, and should be further examined with regard to its anticataract potential.
3-D Nucleus Architecture in Oat × Maize Addition Lines
Authors: Idziak-Helmcke Dominika , Warzecha Tomasz , Sowa Marta , Warchoł Marzena , Dziurka Kinga , Czyczyło-Mysza Ilona , Skrzypek Edyta
Published: June 2020

The nucleus architecture of hybrid crop plants is not a well-researched topic, yet it can have important implications for their genetic stability and usefulness in the successful expression of agronomically desired traits. In this work we studied the spatial distribution of introgressed maize chromatin in oat × maize addition lines with the number of added maize chromosomes varying from one to four. The number of chromosome additions was confirmed by genomic in situ hybridization (GISH). Maize chromosome-specific simple sequence repeat (SSR) markers were used to identify the added chromosomes. GISH on 3-D root and leaf nuclei was performed to assess the number, volume, and position of the maize-chromatin occupied regions. We revealed that the maize chromosome territory (CT) associations of varying degree prevailed in the double disomic lines, while CT separation was the most common distribution pattern in the double monosomic line. In all analyzed lines, the regions occupied by maize CTs were located preferentially at the nuclear periphery. A comparison between the tissues showed that the maize CTs in the leaf nuclei are positioned closer to the center of the nucleus than in the root nuclei. These findings shed more light on the processes that shape the nucleus architecture in hybrids.
Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia
Authors: Kim Sena , Santhanam Srikanth , Lim Sora , Choi Jaebok
Published: June 2020

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main therapeutic strategy for patients with both malignant and nonmalignant disorders. The therapeutic benefits of allo-HSCT in malignant disorders are primarily derived from the graft-versus-leukemia (GvL) effect, in which T cells in the donor graft recognize and eradicate residual malignant cells. However, the same donor T cells can also recognize normal host tissues as foreign, leading to the development of graft-versus-host disease (GvHD), which is difficult to separate from GvL and is the most frequent and serious complication following allo-HSCT. Inhibition of donor T cell toxicity helps in reducing GvHD but also restricts GvL activity. Therefore, developing a novel therapeutic strategy that selectively suppresses GvHD without affecting GvL is essential. Recent studies have shown that inhibition of histone deacetylases (HDACs) not only inhibits the growth of tumor cells but also regulates the cytotoxic activity of T cells. Here, we compile the known therapeutic potential of HDAC inhibitors in preventing several stages of GvHD pathogenesis. Furthermore, we will also review the current clinical features of HDAC inhibitors in preventing and treating GvHD as well as maintaining GvL.
How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review
Authors: Lontay Beata , Kiss Andrea , Virág László , Tar Krisztina
Published: June 2020

Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder characterized by the loss of motor control and cognitive ability, which eventually leads to death. The mutant huntingtin protein (HTT) exhibits an expansion of a polyglutamine repeat. The mechanism of pathogenesis is still not fully characterized; however, evidence suggests that post-translational modifications (PTMs) of HTT and upstream and downstream proteins of neuronal signaling pathways are involved. The determination and characterization of PTMs are essential to understand the mechanisms at work in HD, to define possible therapeutic targets better, and to challenge the scientific community to develop new approaches and methods. The discovery and characterization of a panoply of PTMs in HTT aggregation and cellular events in HD will bring us closer to understanding how the expression of mutant polyglutamine-containing HTT affects cellular homeostasis that leads to the perturbation of cell functions, neurotoxicity, and finally, cell death. Hence, here we review the current knowledge on recently identified PTMs of HD-related proteins and their pathophysiological relevance in the formation of abnormal protein aggregates, proteolytic dysfunction, and alterations of mitochondrial and metabolic pathways, neuroinflammatory regulation, excitotoxicity, and abnormal regulation of gene expression.
Regulation of Actin Filament Length by Muscle Isoforms of Tropomyosin and Cofilin
Authors: Robaszkiewicz Katarzyna , Śliwinska Małgorzata , Moraczewska Joanna
Published: June 2020

In striated muscle the extent of the overlap between actin and myosin filaments contributes to the development of force. In slow twitch muscle fibers actin filaments are longer than in fast twitch fibers, but the mechanism which determines this difference is not well understood. We hypothesized that tropomyosin isoforms Tpm1.1 and Tpm3.12, the actin regulatory proteins, which are specific respectively for fast and slow muscle fibers, differently stabilize actin filaments and regulate severing of the filaments by cofilin-2. Using in vitro assays, we showed that Tpm3.12 bound to F-actin with almost 2-fold higher apparent binding constant (Kapp) than Tpm1.1. Cofilin2 reduced Kapp of both tropomyosin isoforms. In the presence of Tpm1.1 and Tpm3.12 the filaments were longer than unregulated F-actin by 25% and 40%, respectively. None of the tropomyosins affected the affinity of cofilin-2 for F-actin, but according to the linear lattice model both isoforms increased cofilin-2 binding to an isolated site and reduced binding cooperativity. The filaments decorated with Tpm1.1 and Tpm3.12 were severed by cofilin-2 more often than unregulated filaments, but depolymerization of the severed filaments was inhibited. The stabilization of the filaments by Tpm3.12 was more efficient, which can be attributed to lower dynamics of Tpm3.12 binding to actin.
Biotechnological Strategies for Chitosan Production by Mucoralean Strains and Dimorphism Using Renewable Substrates
Authors: de Souza Adriana Ferreira , Galindo Hugo Marques , de Lima Marcos Antônio Barbosa , Ribeaux Daylin Rubio , Rodríguez Dayana Montero , da Silva Andrade Rosileide Fontenele , Gusmão Norma Buarque , de Campos-Takaki Galba Maria
Published: June 2020

We investigated the influence of corn steep liquor (CSL) and cassava waste water (CWW) as carbon and nitrogen sources on the morphology and production of biomass and chitosan by Mucor subtilissimus UCP 1262 and Lichtheimia hyalospora UCP 1266. The highest biomass yields of 4.832 g/L (M. subtilissimus UCP 1262) and 6.345 g/L (L. hyalospora UCP 1266) were produced in assay 2 (6% CSL and 4% CWW), factorial design 22, and also favored higher chitosan production (32.471 mg/g) for M. subtilissimus. The highest chitosan production (44.91 mg/g) by L. hyalospora (UCP 1266) was obtained at the central point (4% of CWW and 6% of CSL). The statistical analysis, the higher concentration of CSL, and lower concentration of CWW significantly contributed to the growth of the strains. The FTIR bands confirmed the deacetylation degree of 80.29% and 83.61% of the chitosan produced by M. subtilissimus (UCP 1262) and L. hyalospora (UCP 1266), respectively. M. subtilissimus (UCP 1262) showed dimorphism in assay 4–6% CSL and 8% CWW and central point. L. hyalospora (UCP 1266) was optimized using a central composite rotational design, and the highest yield of chitosan (63.18 mg/g) was obtained in medium containing 8.82% CSL and 7% CWW. The experimental data suggest that the use of CSL and CWW is a promising association to chitosan production.
High-Speed Atomic Force Microscopy Reveals the Structural Dynamics of the Amyloid-β and Amylin Aggregation Pathways
Authors: Watanabe-Nakayama Takahiro , Sahoo Bikash R. , Ramamoorthy Ayyalusamy , Ono Kenjiro
Published: June 2020

Individual Alzheimer’s disease (AD) patients have been shown to have structurally distinct amyloid-β (Aβ) aggregates, including fibrils, in their brain. These findings suggest the possibility of a relationship between AD progression and Aβ fibril structures. Thus, the characterization of the structural dynamics of Aβ could aid the development of novel therapeutic strategies and diagnosis. Protein structure and dynamics have typically been studied separately. Most of the commonly used biophysical approaches are limited in providing substantial details regarding the combination of both structure and dynamics. On the other hand, high-speed atomic force microscopy (HS-AFM), which simultaneously visualizes an individual protein structure and its dynamics in liquid in real time, can uniquely link the structure and the kinetic details, and it can also unveil novel insights. Although amyloidogenic proteins generate heterogeneously aggregated species, including transient unstable states during the aggregation process, HS-AFM elucidated the structural dynamics of individual aggregates in real time in liquid without purification and isolation. Here, we review and discuss the HS-AFM imaging of amyloid aggregation and strategies to optimize the experiments showing findings from Aβ and amylin, which is associated with type II diabetes, shares some common biological features with Aβ, and is reported to be involved in AD.
Brain Overexpression of Uncoupling Protein-2 (UCP2) Delays Renal Damage and Stroke Occurrence in Stroke-Prone Spontaneously Hypertensive Rats
Authors: Busceti Carla L. , Cotugno Maria , Bianchi Franca , Forte Maurizio , Stanzione Rosita , Marchitti Simona , Battaglia Giuseppe , Nicoletti Ferdinando , Fornai Francesco , Rubattu Speranza
Published: June 2020

The downregulation of uncoupling protein-2 (UCP2) is associated with increased brain and kidney injury in stroke-prone spontaneously hypertensive rats (SHRSP) fed with a Japanese style hypersodic diet (JD). Systemic overexpression of UCP2 reduces organ damage in JD-fed SHRSP. We examined the effect of brain-specific UCP2 overexpression on blood pressure (BP), stroke occurrence and kidney damage in JD-fed SHRSP. Rats received a single i.c.v. injection of a lentiviral vector encoding UCP2 (LV-UCP2), or an empty vector. The brain delivery of LV-UCP2 significantly delayed the occurrence of stroke and kidney damage. The large reduction of proteinuria observed after LV-UCP2 injection was unexpected, because BP levels were unchanged. At the time of stroke, rats treated with LV-UCP2 still showed a large UCP2 upregulation in the striatum, associated with increases in OPA1 and FIS1 protein levels, and reductions in PGC1-α, SOD2, TNFα mRNA levels and NRF2 protein levels. This suggested UCP2 overexpression enhanced mitochondrial fusion and fission and reduced oxidative damage and inflammation in the striatum of JD-fed SHRSP rats. Our data suggest the existence of central mechanisms that may protect against hypertension-induced organ damage independently of BP, and strengthen the suitability of strategies aimed at enhancing UCP2 expression for the treatment of hypertensive damage.
Novel Therapies Boosting T Cell Immunity in Epstein Barr Virus-Associated Nasopharyngeal Carcinoma
Authors: Renaud Sarah , Lefebvre Anthony , Mordon Serge , Moralès Olivier , Delhem Nadira
Published: June 2020

Nasopharyngeal carcinoma (NPC) is a malignant tumour of the head and neck affecting localised regions of the world, with the highest rates described in Southeast Asia, Northern Africa, and Greenland. Its high morbidity rate is linked to both late-stage diagnosis and unresponsiveness to conventional anti-cancer treatments. Multiple aetiological factors have been described including environmental factors, genetics, and viral factors (Epstein Barr Virus, EBV), making NPC treatment that much more complex. The most common forms of NPCs are those that originate from the epithelial tissue lining the nasopharynx and are often linked to EBV infection. Indeed, they represent 75–95% of NPCs in the low-risk populations and almost 100% of NPCs in high-risk populations. Although conventional surgery has been improved with nasopharyngectomy’s being carried out using more sophisticated surgical equipment for better tumour resection, recent findings in the tumour microenvironment have led to novel treatment options including immunotherapies and photodynamic therapy, able to target the tumour and improve the immune system. This review provides an update on the disease’s aetiology and the future of NPC treatments with a focus on therapies activating T cell immunity.
Cellular Models and Assays to Study NLRP3 Inflammasome Biology
Authors: Zito Giovanni , Buscetta Marco , Cimino Maura , Dino Paola , Bucchieri Fabio , Cipollina Chiara
Published: June 2020

The NLRP3 inflammasome is a multi-protein complex that initiates innate immunity responses when exposed to a wide range of stimuli, including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Inflammasome activation leads to the release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and to pyroptotic cell death. Over-activation of NLRP3 inflammasome has been associated with several chronic inflammatory diseases. A deep knowledge of NLRP3 inflammasome biology is required to better exploit its potential as therapeutic target and for the development of new selective drugs. To this purpose, in the past few years, several tools have been developed for the biological characterization of the multimeric inflammasome complex, the identification of the upstream signaling cascade leading to inflammasome activation, and the downstream effects triggered by NLRP3 activation. In this review, we will report cellular models and cellular, biochemical, and biophysical assays that are currently available for studying inflammasome biology. A special focus will be on those models/assays that have been used to identify NLRP3 inhibitors and their mechanism of action.
Class I KNOX Is Related to Determinacy during the Leaf Development of the Fern Mickelia scandens (Dryopteridaceae)
Authors: Cruz Rafael , Melo-de-Pinna Gladys F. A. , Vasco Alejandra , Prado Jefferson , Ambrose Barbara A.
Published: June 2020

Unlike seed plants, ferns leaves are considered to be structures with delayed determinacy, with a leaf apical meristem similar to the shoot apical meristems. To better understand the meristematic organization during leaf development and determinacy control, we analyzed the cell divisions and expression of Class I KNOX genes in Mickelia scandens, a fern that produces larger leaves with more pinnae in its climbing form than in its terrestrial form. We performed anatomical, in situ hybridization, and qRT-PCR experiments with histone H4 (cell division marker) and Class I KNOX genes. We found that Class I KNOX genes are expressed in shoot apical meristems, leaf apical meristems, and pinnae primordia. During early development, cell divisions occur in the most distal regions of the analyzed structures, including pinnae, and are not restricted to apical cells. Fern leaves and pinnae bear apical meristems that may partially act as indeterminate shoots, supporting the hypothesis of homology between shoots and leaves. Class I KNOX expression is correlated with indeterminacy in the apex and leaf of ferns, suggesting a conserved function for these genes in euphyllophytes with compound leaves.
CAIX-Mediated Control of LIN28/let-7 Axis Contributes to Metabolic Adaptation of Breast Cancer Cells to Hypoxia
Authors: Gibadulinova Adriana , Bullova Petra , Strnad Hynek , Pohlodek Kamil , Jurkovicova Dana , Takacova Martina , Pastorekova Silvia , Svastova Eliska
Published: June 2020

Solid tumors, including breast cancer, are characterized by the hypoxic microenvironment, extracellular acidosis, and chemoresistance. Hypoxia marker, carbonic anhydrase IX (CAIX), is a pH regulator providing a selective survival advantage to cancer cells through intracellular neutralization while facilitating tumor invasion by extracellular acidification. The expression of CAIX in breast cancer patients is associated with poor prognosis and metastases. Importantly, CAIX-positive hypoxic tumor regions are enriched in cancer stem cells (CSCs). Here we investigated the biological effects of CA9-silencing in breast cancer cell lines. We found that CAIX-downregulation in hypoxia led to increased levels of let-7 (lethal-7) family members. Simultaneously with the increase of let-7 miRNAs in CAIX-suppressed cells, LIN28 protein levels decreased, along with downstream metabolic pathways: pyruvate dehydrogenase kinase 1 (PDK1) and phosphorylation of its substrate, pyruvate dehydrogenase (PDH) at Ser-232, causing attenuation of glycolysis. In addition to perturbed glycolysis, CAIX-knockouts, in correlation with decreased LIN28 (as CSC reprogramming factor), also exhibit reduction of the further CSC-associated markers NANOG (Homeobox protein NANOG) and ALDH1 (Aldehyde dehydrogenase isoform 1). Oppositely, overexpression of CAIX leads to the enhancement of LIN28, ALDH1, and NANOG. In conclusion, CAIX-driven regulation of the LIN28/let-7 axis augments glycolytic metabolism and enhances stem cell markers expression during CAIX-mediated adaptation to hypoxia and acidosis in carcinogenesis.
AndroDFA: Android Malware Classification Based on Resource Consumption
Authors: Massarelli Luca , Aniello Leonardo , Ciccotelli Claudio , Querzoni Leonardo , Ucci Daniele , Baldoni Roberto
Published: June 2020

The vast majority of today’s mobile malware targets Android devices. An important task of malware analysis is the classification of malicious samples into known families. In this paper, we propose AndroDFA (DFA, detrended fluctuation analysis): an approach to Android malware family classification based on dynamic analysis of resource consumption metrics available from the proc file system. These metrics can be easily measured during sample execution. From each malware, we extract features through detrended fluctuation analysis (DFA) and Pearson’s correlation, then a support vector machine is employed to classify malware into families. We provide an experimental evaluation based on malware samples from two datasets, namely Drebin and AMD. With the Drebin dataset, we obtained a classification accuracy of 82%, comparable with works from the state-of-the-art like DroidScribe. However, compared to DroidScribe, our approach is easier to reproduce because it is based on publicly available tools only, does not require any modification to the emulated environment or Android OS, and by design, can also be used on physical devices rather than exclusively on emulators. The latter is a key factor because modern mobile malware can detect the emulated environment and hide its malicious behavior. The experiments on the AMD dataset gave similar results, with an overall mean accuracy of 78%. Furthermore, we made the software we developed publicly available, to ease the reproducibility of our results.
Transgenic Ectopic Overexpression of Broad Complex (BrC-Z2) in the Silk Gland Inhibits the Expression of Silk Fibroin Genes of Bombyx mori
Authors: Cong Jiangshan , Tao Cuicui , Zhang Xuan , Zhang Hui , Cheng Tingcai , Liu Chun
Published: June 2020

Bombyx mori silk protein genes are strictly turned on and off in different developmental stages under the hormone periodically change. The broad complex (BrC) is a transcription factor mediating 20-hydroxyecdysone action, which plays important roles during metamorphosis. Here, we observed that two isoforms of BmBrC (BmBrC-Z2 and BmBrC-Z4) exhibited contrasting expression patterns with fibroin genes (FibH, FibL and P25) in the posterior silk gland (PSG), suggesting that BmBrC may negatively regulate fibroin genes. Transgenic lines were constructed to ectopically overexpress BmBrC-Z2 in the PSG. The silk protein genes in the transgenic line were decreased to almost half of that in the wild type. The silk yield was decreased significantly. In addition, the expression levels of regulatory factors (BmKr-h1 and BmDimm) response to juvenile hormone (JH) signal were inhibited significantly. Then exogenous JH in the BmBrC-Z2 overexpressed lines can inhibit the expression of BmBrC-Z2 and activate the expression of silk protein genes and restore the silk yield to the level of the wild type. These results indicated that BmBrC may inhibit fibroin genes by repressing the JH signal pathway, which would assist in deciphering the comprehensive regulation mechanism of silk protein genes.
Evaluation of Innate Immune Mediators Related to Respiratory Viruses in the Lung of Stable COPD Patients
Authors: D’Anna Silvestro E. , Maniscalco Mauro , Carriero Vitina , Gnemmi Isabella , Caramori Gaetano , Nucera Francesco , Righi Luisella , Brun Paola , Balbi Bruno , Adcock Ian M , Stella Maria Grazia , Ricciardolo Fabio L.M. , Di Stefano Antonino
Published: June 2020

Background: Little is known about the innate immune response to viral infections in stable Chronic Obstructive Pulmonary Disease (COPD). Objectives: To evaluate the innate immune mediators related to respiratory viruses in the bronchial biopsies and lung parenchyma of stable COPD patients. Methods: We evaluated the immunohistochemical (IHC) expression of Toll-like receptors 3-7-8-9 (TLR-3-7-8-9), TIR domain-containing adaptor inducing IFNβ (TRIF), Interferon regulatory factor 3 (IRF3), Phospho interferon regulatory factor 3  ( pIRF3), Interferon regulatory factor 7 (IRF7), Phospho interferon regulatory factor 7 (pIRF7), retinoic acid-inducible gene I (RIG1), melanoma differentiation-associated protein 5 (MDA5), Probable ATP-dependent RNA helicase DHX58 ( LGP2), Mitochondrial antiviral-signaling protein (MAVS), Stimulator of interferon genes (STING), DNA-dependent activator of IFN regulatory factors (DAI), forkhead box protein A3(FOXA3), Interferon alfa (IFNα), and Interferon beta (IFNβ) in the bronchial mucosa of patients with mild/moderate (n = 16), severe/very severe (n = 18) stable COPD, control smokers (CS) (n = 12), and control non-smokers (CNS) (n = 12). We performed similar IHC analyses in peripheral lung from COPD (n = 12) and CS (n = 12). IFNα and IFNβ were assessed in bronchoalveolar lavage (BAL) supernatant from CNS (n = 8), CS (n = 9) and mild/moderate COPD (n = 12). Viral load, including adenovirus-B, -C, Bocavirus, Respiratory syncytial Virus (RSV),Human Rhinovirus (HRV), Coronavirus, Influenza virus A (FLU-A), Influenza virus B (FLU-B), and Parainfluenzae-1 were measured in bronchial rings and lung parenchyma of COPD patients and the related control group (CS). Results: Among the viral-related innate immune mediators, RIG1, LGP2, MAVS, STING, and DAI resulted well expressed in the bronchial and lung tissues of COPD patients, although not in a significantly different mode from control groups. Compared to CS, COPD patients showed no significant differences of viral load in bronchial rings and lung parenchyma. Conclusions: Some virus-related molecules are well-expressed in the lung tissue and bronchi of stable COPD patients independently of the disease severity, suggesting a “primed” tissue environment capable of sensing the potential viral infections occurring in these patients.
Idiosyncratic Drug-Induced Neutropenia and Agranulocytosis in Elderly Patients
Authors: Lorenzo-Villalba Noel , Alonso-Ortiz Maria Belen , Maouche Yasmine , Zulfiqar Abrar-Ahmad , Andrès Emmanuel
Published: June 2020

Agranulocytosis is a rare, but serious and life-threatening hematologic disorder in elderly patients. Idiosyncratic drug-induced agranulocytosis (IDIA) has been classically defined by a neutrophil count below 0.5 × 109/L. The annual incidence of IDIA in Europe is about 1.6–9.2 cases per million inhabitants. Increasing age and female sex have been considered as risk factors for the development of this condition. Besides, it is well known that older people take on average more drugs than younger people. This condition is most often associated with the intake of antibacterial agents, antiplatelets, antithyroids, antipsychotics, antiepileptics and nonsteroidal anti-inflammatory drugs (NSAIDs). Initially, agranulocytosis may present without symptoms, but may quickly progress to a severe infection and sepsis. The causative drug should be immediately stopped. In febrile patients, blood cultures and where indicated, site-specific cultures should be obtained and early treatment with empirical broad-spectrum antibiotics started. Even with adequate treatment, the mortality rate is higher in elderly patients reaching up to 20%. Hematopoietic growth factors have proven to be useful as they shorten the duration of neutropenia. However, data on neutropenia and agranulocytosis in the elderly meeting the criteria of evidence-based medicine are still poor in the literature. This review analyzes the results of our experience as well as other published studies of the universal literature.
Outpatient Pulmonary Rehabilitation in Patients with Persisting Symptoms after Pulmonary Embolism
Authors: Nopp Stephan , Klok Frederikus A. , Moik Florian , Petrovic Milos , Derka Irmgard , Ay Cihan , Zwick Ralf Harun
Published: June 2020

Background: Patients with pulmonary embolism (PE) may suffer from long-term consequences, including decreased functional capacity. Data on pulmonary rehabilitation (PR) in patients with PE are scarce, and no data on outpatient PR are available so far. Methods: We analyzed data of 22 PE patients who attended outpatient PR due to exertional dyspnea. Patients underwent a multi-professional 6-week PR program. The primary outcome was change in 6-min walk test (6MWT). Secondary outcomes included changes in strength and endurance tests. To assess long-term benefits, follow-up was performed a median of 39 months after PR. Results: Patients started PR a median of 19 weeks after the acute PE event. Their median age was 47.5 years, 33% were women and all presented with NYHA (New York Heart Association) class II and higher. After PR, patients showed significant and clinically relevant improvements in 6MWT (mean difference: 49.4 m [95% CI 32.0−66.8]). Similarly, patients increased performance in maximum strength, endurance and inspiratory muscle strength. At long-term follow-up, 78% of patients reported improved health. Conclusion: We observed significant improvements in exercise capacity in PE patients undergoing outpatient PR. The majority of patients also reported a long-term improvement in health status. Prospective studies are needed to identify patients who would benefit most from structured PR.
Use of Antimalarial Agents Is Associated with Favourable Physical Functioning in Patients with Systemic Lupus Erythematosus
Authors: Gomez Alvaro , Soukka Sofia , Johansson Petter , Åkerström Emil , Emamikia Sharzad , Enman Yvonne , Chatzidionysiou Katerina , Parodis Ioannis
Published: June 2020

Impaired health-related quality of life (HRQoL) is a major problem in patients with systemic lupus erythematosus (SLE). Antimalarial agents (AMA) are the cornerstone of SLE therapy, but data on their impact on HRQoL are scarce. We investigated this impact using baseline data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials (n = 1684). HRQoL was self-reported using the Medical Outcomes Study short-form 36 (SF-36), functional assessment of chronic illness therapy (FACIT)-Fatigue and 3-level EuroQoL 5-Dimension (EQ-5D) questionnaires. Patients on AMA (n = 1098/1684) performed better with regard to SF-36 physical component summary, physical functioning, role physical, bodily pain, FACIT-Fatigue, EQ-5D utility index and EQ-5D visual analogue scale scores. The difference in SF-36 physical functioning (mean ± standard deviation (SD): 61.1 ± 24.9 versus 55.0 ± 26.5; p < 0.001) exceeded the minimal clinically important difference (≥5.0). This association remained significant after adjustment for potential confounding factors in linear regression models (standardised coefficient, β = 0.07; p = 0.002). Greater proportions of AMA users than non-users reported no problems in the mobility, self-care, usual activities and anxiety/depression EQ-5D dimensions. AMA use was particularly associated with favourable HRQoL in physical aspects among patients with active mucocutaneous and musculoskeletal disease, and mental aspects among patients with active renal SLE. These results provide support in motivating adherence to AMA therapy. Exploration of causality in the relationship between AMA use and favourable HRQoL in SLE has merit.
Sialylation of Human Natural Killer (NK) Cells Is Regulated by IL-2
Authors: Rosenstock Philip , Bork Kaya , Massa Chiara , Selke Philipp , Seliger Barbara , Horstkorte Rüdiger
Published: June 2020

Sialic acids are terminal sugars on the cell surface that are found on all cell types including immune cells like natural killer (NK) cells. The attachment of sialic acids to different glycan structures is catalyzed by sialyltransferases in the Golgi. However, the expression pattern of sialyltransferases in NK cells and their expression after activation has not yet been analyzed. Therefore, the present study determines which sialyltransferases are expressed in human NK cells and if activation with IL-2 changes the sialylation of NK cells. The expression of sialyltransferases was analyzed in the three human NK cell lines NK-92, NKL, KHYG-1 and primary NK cells. NK-92 cells were cultured in the absence or presence of IL-2, and changes in the sialyltransferase expression were measured by qPCR. Furthermore, specific sialylation was investigated by flow cytometry. In addition, polySia and NCAM were measured by Western blot analyses. IL-2 leads to a reduced expression of ST8SIA1, ST6GAL1 and ST3GAL1. α-2,3-Sialylation remained unchanged, while α-2,6-sialylation was increased after IL-2 stimulation. Moreover, an increase in the amount of NCAM and polySia was observed in IL-2-activated NK cells, whereas GD3 ganglioside was decreased. In this study, all sialyltransferases that were expressed in NK cells could be identified. IL-2 regulates the expression of some sialyltransferases and leads to changes in the sialylation of NK cells.
Always Online? Internet Addiction and Social Impairment in Psoriasis across Germany
Authors: Schielein Maximilian Christian , Tizek Linda , Schuster Barbara , Ziehfreund Stefanie , Liebram Claudia , Eyerich Kilian , Zink Alexander
Published: June 2020

With the World Health Organization (WHO) demanding further investigation of the social impairment and psychosocial burden of psoriasis, a first study identified a high prevalence of Internet addiction. The aim of this study was to assess social impairment and estimate the occurrence of Internet addiction along with depression, cigarette smoking, and alcohol dependency in individuals with psoriasis recruited online in a people-centered care approach. A cross-sectional online survey was carried out across Germany between March 2019 and June 2019. The questionnaire contained information on social impairment, smoking habits, as well as validated questionnaires on Internet addiction, depression, and alcohol dependency. Overall, 460 individuals (62.4% female; mean age: 45.9 ± 13.7 years) with psoriasis were included. Of those, 406 (88.3%) stated to be at least rarely socially impaired. The positive screening rate for Internet addiction was 8.5%. Furthermore, 40.0% had positive screenings for depression, 17.1% for alcohol dependency, and 32.6% for daily smoking. Positive screenings for Internet addiction and alcohol dependency were substantially more frequent in individuals with psoriasis than in the German general population. In order to meet the demands of the WHO, Internet addiction could be considered as a potential comorbidity in psoriasis and a focus on people-centered care is advisable for further research.
Functional Assessment and Patient-Related Outcomes after Gluteus Maximus Flap Transfer in Patients with Severe Hip Abductor Deficiency
Authors: Ruckenstuhl Paul , Wassilew Georgi I. , Müller Michael , Hipfl Christian , Pumberger Matthias , Perka Carsten , Hardt Sebastian
Published: June 2020

(1) Background: Degeneration of the hip abductor mechanism, a well-known cause of functional limitation, is difficult to treat and is associated with a reduced health-related quality of life (HRQOL). The gluteus maximus muscle flap is a treatment option to support a severely degenerative modified gluteus medius muscle. Although several reports exist on the clinical outcome, there remains a gap in the literature regarding HRQOL in conjunction with functional results. (2) Methods: The present study consists of 18 patients with a mean age of 64 (53‒79) years, operatively treated with a gluteus maximus flap due to chronic gluteal deficiency. Fifteen (83%) of these patients presented a history of total hip arthroplasty or revision arthroplasty. Pre and postoperative pain, Trendelenburg sign, internal rotation lag sign, trochanteric pain syndrome, the Harris Hip Score (HHS), and abduction strength after Janda (0‒5) were evaluated. Postoperative patient satisfaction and health-related quality of life, according to the Short Form 36 (SF-36), were used as patient-reported outcome measurements (PROMs). Postoperative MRI scans were performed in 13 cases (72%). (3) Results: Local pain decreased from NRS 6.1 (0–10) to 4.9 (0–8) and 44% presented with a negative Trendelenburg sign postoperatively. The overall HHS results (p = 0.42) and muscular abduction strength (p = 0.32) increased without significance. The postoperative HRQOL reached 46.8 points (31.3–62.6) for the mental component score and 37.1 points (26.9–54.7) for the physical component score. The physical component results presented a high level of positive correlation with HHS scores postoperatively (R = 0.88, p < 0.001). Moreover, 72% reported that they would undergo the operative treatment again. The MRI overall showed no significant further loss of muscle volume and no further degeneration of muscular tissue. (4) Conclusions: Along with fair functional results, the patients treated with a gluteus maximus flap transfer presented satisfying long-term PROMs. Given this condition, the gluteus maximus muscle flap transfer is a viable option for selected patients with chronic gluteal deficiency.
Bilateral Fundus Excyclotorsion in Unilateral Superior Oblique Palsy Confirmed by MR Imaging
Authors: Hong Eun Hee , Yang Hee Kyung , Kim Jae Hyoung , Hwang Jeong-Min
Published: June 2020

Purpose: To determine whether bilateral fundus excyclotorsion is helpful in distinguishing bilateral superior oblique palsy (SOP) from unilateral SOP by investigating bilateral fundus excyclotorsion in unilateral SOP and comparing the features with bilateral SOP using fundus photographs. Methods: This retrospective cohort study included a total of 212 subjects who were diagnosed with unilateral SOP with hypoplasia of a single superior oblique (SO) muscle and 7 subjects with clinically diagnosed bilateral SOP. Fundus excyclotorsion measured by modified fovea–disc angles and inter-eye differences in cyclotorsion angles (the difference in fundus excyclotorsion angles: paretic eye or hypertropic eye in primary gaze–fellow eye), and subjective cyclotorsion were compared between groups of unilateral SOP with bilateral fundus excyclotorsion (SOPBE) and bilateral SOP. Results: Bilateral fundus excyclotorsion was found in 18 out of 212 patients (8.5%) in the unilateral SOP group, and 7 out of 7 patients (100%) in the bilateral SOP group. Among the 25 patients with bilateral fundus excyclotorsion, the mean angle of excyclotorsion (5.7° ± 4.7° vs. 7.6° ± 4.3°, p = 0.125) and the inter-eye differences (0.7° ± 3.6° vs. 0.5° ± 5.8°, p = 0.615) were not significantly different between the unilateral SOPBE and bilateral SOP groups. The degree of subjective excyclotorsion was significantly larger in the bilateral SOP group compared with the unilateral SOPBE group (16.0 ± 5.5 vs. 4.6 ± 4.3, p = 0.002). Conclusion: Bilateral fundus excyclotorsion was demonstrated not only in bilateral SOP, but also in unilateral SOP at a rate of 8.5%. Bilateral fundus excyclotorsion alone did not prove to be a specific sign in distinguishing bilateral SOP from unilateral SOP.