bluuebunny/crossref_metadata_2025 huggingface dataset:
Canonical and Divergent N-Terminal HBx Isoform Proteins Unveiled: Characteristics and Roles during HBV Replication
Authors: Hernández Sergio , Álvarez-Astudillo Francisca , Garrido Daniel , Prieto Cristian , Loyola Alejandra , Villanueva Rodrigo A.
Published: November 2021

Hepatitis B virus (HBV) X protein (HBx) is a viral regulatory and multifunctional protein. It is well-known that the canonical HBx reading frame bears two phylogenetically conserved internal in-frame translational initiation codons at Met2 and Met3, thus possibly generating divergent N-terminal smaller isoforms during translation. Here, we demonstrate that the three distinct HBx isoforms are generated from the ectopically expressed HBV HBx gene, named XF (full-length), XM (medium-length), and XS (short-length); they display different subcellular localizations when expressed individually in cultured hepatoma cells. Particularly, the smallest HBx isoform, XS, displayed a predominantly cytoplasmic localization. To study HBx proteins during viral replication, we performed site-directed mutagenesis to target the individual or combinatorial expression of the HBx isoforms within the HBV viral backbone (full viral genome). Our results indicate that of all HBx isoforms, only the smallest HBx isoform, XS, can restore WT levels of HBV replication, and bind to the viral mini chromosome, thereby establishing an active chromatin state, highlighting its crucial activities during HBV replication. Intriguingly, we found that sequences of HBV HBx genotype H are devoid of the conserved Met3 position, and therefore HBV genotype H infection is naturally silent for the expression of the HBx XS isoform. Finally, we found that the HBx XM (medium-length) isoform shares significant sequence similarity with the N-terminus domain of the COMMD8 protein, a member of the copper metabolism MURR1 domain-containing (COMMD) protein family. This novel finding might facilitate studies on the phylogenetic origin of the HBV X protein. The identification and functional characterization of its isoforms will shift the paradigm by changing the concept of HBx from being a unique, canonical, and multifunctional protein toward the occurrence of different HBx isoforms, carrying out different overlapping functions at different subcellular localizations during HBV genome replication. Significantly, our current work unveils new crucial HBV targets to study for potential antiviral research, and human virus pathogenesis.
Posttranslational Modifications in PD-L1 Turnover and Function: From Cradle to Grave
Authors: Yu Xinfang , Li Wei , Young Ken H. , Li Yong
Published: November 2021

Programmed death-ligand 1 (PD-L1) is one of the most classic immune checkpoint molecules. Cancer cells express PD-L1 to inhibit the activity of effector T cells’ cytotoxicity through programmed death 1 (PD-1) engagement in exposure to inflammatory cytokines. PD-L1 expression levels on cancer cells might affect the clinical response to anti-PD-1/PD-L1 therapies. Hence, understanding molecular mechanisms for regulating PD-L1 expression is essential for improving the clinical response rate and efficacy of PD-1/PD-L1 blockade. Posttranslational modifications (PTMs), including phosphorylation, glycosylation, ubiquitination, and acetylation, regulate PD-L1 stability, cellular translocation, and interaction with its receptor. A coordinated positive and negative regulation via PTMs is required to ensure the balance and function of the PD-L1 protein. In this review, we primarily focus on the roles of PTMs in PD-L1 expression, trafficking, and antitumor immune response. We also discuss the implication of PTMs in anti-PD-1/PD-L1 therapies.
Sustainability Assessment of the Anthropogenic System in Panama City: Application of Biomimetic Strategies towards Regenerative Cities
Authors: Quintero Andrea , Zarzavilla Marichell , Tejedor-Flores Nathalia , Mora Dafni , Chen Austin Miguel
Published: November 2021

To understand the sustainability problem for Panama’s metropolitan area, its urban metabolism was investigated. A way to evaluate its current state was obtained by estimating a sustainable indicator based on the Green City Index. With the abstraction of the identified problems, the biomimetic strategy “problem-based approach” was carried out, where different pinnacles of nature were selected as a reference for the design of regenerative solutions. These were inspired by the understanding of the living world and how to include ecosystems in urban designs. Therefore, a framework was proposed for positive generation and natural solutions in cities to take advantage of the regenerative potential in Panama City. Using ecosystem services, a set of indicators were developed to measure regeneration over the years at the city scale. The results indicate that from the 11 selected pinnacles, 17 solutions inspired in nature were proposed to regenerate cities. Consequently, a SWOT analysis was realized along with a questionnaire by experts from different fields. The findings obtained show that the feasible solutions were: arborization, green facades, solar roofs, e-mobility, green corridors, bicycle lanes, sidewalks, and biofilters. This research represents a step towards creating and developing regenerative cities, thus improving the quality of life of living beings and ecosystems present in society.
Alterations of Plasma Galectin-3 and C3 Levels in Patients with Parkinson’s Disease
Authors: Wu Hsiu-Chuan , Chang Kuo-Hsuan , Chiang Mu-Chun , Chen Chiung-Mei
Published: November 2021

Parkinson’s disease (PD) is characterized by progressive neurodegeneration of dopaminergic neurons in the ventral midbrain. The complement-phagosome pathway is involved in the pathogenesis of PD. Here we measured levels of complement-phagocytosis molecules, including galectin-3, C3, C4, and cathepsin D, in the plasma of 56 patients with PD, and 46 normal controls (NCs). Plasma levels of galectin-3 (9.93 ± 3.94 ng/mL) were significantly higher in PD patients compared with NCs (8.39 ± 1.95 ng/mL, p = 0.012), and demonstrated a positive correlation with Hoehn and Yahr stages in PD patients (R2 = 0.218, p < 0.001). On the other hand, plasma C3 levels were significantly lower in PD patients (305.27 ± 205.16 μg/mL) compared with NCs (444.34 ± 245.54 μg/mL, p = 0.002). However, the levels did not correlate with Hoehn and Yahr stages (R2 = 0.010, p = 0.469). Plasma levels of C4 and cathepsin D in PD patients were similar to those in NCs. Our results show possible altered complement-phagocytosis signals in the peripheral blood of PD patients, highlighting the potential of galectin-3 as a biomarker of PD.
Predicting the Extent of Resection of Motor-Eloquent Gliomas Based on TMS-Guided Fiber Tracking
Authors: Belotti Francesco , Tuncer Mehmet Salih , Rosenstock Tizian , Ivren Meltem , Vajkoczy Peter , Picht Thomas
Published: November 2021

Background: Surgical planning with nTMS-based tractography is proven to increase safety during surgery. A preoperative risk stratification model has been published based on the M1 infiltration, RMT ratio, and tumor to corticospinal tract distance (TTD). The correlation of TTD with corticospinal tract to resection cavity distance (TRD) and outcome is needed to further evaluate the validity of the model. Aim of the study: To use the postop MRI-derived resection cavity to measure how closely the resection cavity approximated the preoperatively calculated corticospinal tract (CST) and how this correlates with the risk model and the outcome. Methods: We included 183 patients who underwent nTMS-based DTI and surgical resection for presumed motor-eloquent gliomas. TTD, TRD, and motor outcome were recorded and tested for correlations. The intraoperative monitoring documentation was available for a subgroup of 48 patients, whose responses were correlated to TTD and TRD. Results: As expected, TTD and TRD showed a good correlation (Spearman’s ρ = 0.67, p < 0.001). Both the TTD and the TRD correlated significantly with the motor outcome at three months (Kendall’s Tau-b 0.24 for TTD, 0.31 for TRD, p < 0.001). Interestingly, the TTD and TRD correlated only slightly with residual tumor volume, and only after correction for outliers related to termination of resection due to intraoperative monitoring events or the proximity of other eloquent structures (TTD ρ = 0.32, p < 0.001; TRD ρ = 0.19, p = 0.01). This reflects the fact that intraoperative monitoring (IOM) phenomena do not always correlate with preoperative structural analysis, and that additional factors influence the intraoperative decision to abort resection, such as the adjacency of other vulnerable structures. The TTD was also significantly correlated with variations in motor evoked potential (MEP) responses (no/reversible decrease vs. irreversible decrease; p = 0.03). Conclusions: The TTD approximates the TRD well, confirming the best predictive parameter and giving strength to the nTMS-based risk stratification model. Our analysis of TRD supports the use of the nTMS-based TTD measurement to estimate the resection preoperatively, also confirming the 8 mm cutoff. Nevertheless, the TRD proved to have a slightly stronger correlation with the outcome as the surgeon’s experience, anatomofunctional knowledge, and MEP observations influence the expected EOR.
Numerical Simulation of Single-Point Mount PZT-Interface for Admittance-Based Anchor Force Monitoring
Authors: Nguyen Trung-Hau , Phan Thi Tuong Vy , Le Thanh-Cao , Ho Duc-Duy , Huynh Thanh-Canh
Published: November 2021

This study investigates the dynamic characteristics of a smart PZT interface mounted on a prestressed anchorage to verify the numerical feasibility of the admittance-based anchor force monitoring technique. Firstly, the admittance-based anchor force monitoring technique through a single-mount PZT interface is outlined. The admittance response of the PZT interface-anchorage system is theoretically derived to show the proof-of-concept of the technique for anchor force monitoring. Secondly, a finite element model corresponding to a well-established experimental model in the literature is constructed. The effect of anchor force is equivalently treated by the contact stiffness and damping parameters at the bottom surface of the anchorage. Thirdly, the admittance and the impedance responses are numerically analyzed and compared with the experimental data to evaluate the accuracy of the numerical modelling technique. Fourthly, the local dynamics of the PZT interface are analyzed by modal analysis to determine vibration modes that are sensitive to the change in the contact stiffness (i.e., representing the anchor force). Finally, the admittance responses corresponding to the sensitive vibration modes are numerically analyzed under the change in the contact stiffness. The frequency shift and the admittance change are quantified by statistical damage indices to verify the numerical feasibility of the anchor force monitoring technique via the smart PZT interface. The study is expected to provide a reference numerical model for the design of the single-point mount PZT interface.
Targeted Selected Reaction Monitoring Verifies Histology Specific Peptide Signatures in Epithelial Ovarian Cancer
Authors: Liljedahl Leena , Malmström Johan , Kristjansdottir Björg , Waldemarson Sofia , Sundfeldt Karin
Published: November 2021

Epithelial ovarian cancer (OC) is a disease with high mortality due to vague early clinical symptoms. Benign ovarian cysts are common and accurate diagnosis remains a challenge because of the molecular heterogeneity of OC. We set out to investigate whether the disease diversity seen in ovarian cyst fluids and tumor tissue could be detected in plasma. Using existing mass spectrometry (MS)-based proteomics data, we constructed a selected reaction monitoring (SRM) assay targeting peptides from 177 cancer-related and classical proteins associated with OC. Plasma from benign, borderline, and malignant ovarian tumors were used to verify expression (n = 74). Unsupervised and supervised multivariate analyses were used for comparisons. The peptide signatures revealed by the supervised multivariate analysis contained 55 to 77 peptides each. The predictive (Q2) values were higher for benign vs. low-grade serous Q2 = 0.615, mucinous Q2 = 0.611, endometrioid Q2 = 0.428 and high-grade serous Q2 = 0.375 (stage I–II Q2 = 0.515; stage III Q2 = 0.43) OC compared to benign vs. all malignant Q2 = 0.226. With targeted SRM MS we constructed a multiplexed assay for simultaneous detection and relative quantification of 185 peptides from 177 proteins in only 20 µL of plasma. With the approach of histology-specific peptide patterns, derived from pre-selected proteins, we may be able to detect not only high-grade serous OC but also the less common OC subtypes.
3D Breast Tumor Models for Radiobiology Applications
Authors: Ravichandran Akhilandeshwari , Clegg Julien , Adams Mark N. , Hampson Madison , Fielding Andrew , Bray Laura J.
Published: November 2021

Breast cancer is a leading cause of cancer-associated death in women. The clinical management of breast cancers is normally carried out using a combination of chemotherapy, surgery and radiation therapy. The majority of research investigating breast cancer therapy until now has mainly utilized two-dimensional (2D) in vitro cultures or murine models of disease. However, there has been significant uptake of three-dimensional (3D) in vitro models by cancer researchers over the past decade, highlighting a complimentary model for studies of radiotherapy, especially in conjunction with chemotherapy. In this review, we underline the effects of radiation therapy on normal and malignant breast cells and tissues, and explore the emerging opportunities that pre-clinical 3D models offer in improving our understanding of this treatment modality.
Blood Cytokine Analysis Suggests That SARS-CoV-2 Infection Results in a Sustained Tumour Promoting Environment in Cancer Patients
Authors: De Winter Fien H. R. , Hotterbeekx An , Huizing Manon T. , Konnova Angelina , Fransen Erik , Jongers Bart ’s , Jairam Ravi Kumar , Van averbeke Vincent , Moons Pieter , Roelant Ella , Le Blon Debbie , Vanden Berghe Wim , Janssens Annelies , Lybaert Willem , Croes Lieselot , Vulsteke Christof , Malhotra-Kumar Surbhi , Goossens Herman , Berneman Zwi , Peeters Marc , van Dam Peter A. , Kumar-Singh Samir
Published: November 2021

Cytokines, chemokines, and (angiogenic) growth factors (CCGs) have been shown to play an intricate role in the progression of both solid and haematological malignancies. Recent studies have shown that SARS-CoV-2 infection leads to a worse outcome in cancer patients, especially in haematological malignancy patients. Here, we investigated how SARS-CoV-2 infection impacts the already altered CCG levels in solid or haematological malignancies, specifically, whether there is a protective effect or rather a potentially higher risk for major COVID-19 complications in cancer patients due to elevated CCGs linked to cancer progression. Serially analysing immune responses with 55 CCGs in cancer patients under active treatment with or without SARS-CoV-2 infection, we first showed that cancer patients without SARS-CoV-2 infection (n = 54) demonstrate elevated levels of 35 CCGs compared to the non-cancer, non-infected control group of health care workers (n = 42). Of the 35 CCGs, 19 were common to both the solid and haematological malignancy groups and comprised previously described cytokines such as IL-6, TNF-α, IL-1Ra, IL-17A, and VEGF, but also several less well described cytokines/chemokines such as Fractalkine, Tie-2, and T cell chemokine CTACK. Importantly, we show here that 7 CCGs are significantly altered in SARS-CoV-2 exposed cancer patients (n = 52). Of these, TNF-α, IFN-β, TSLP, and sVCAM-1, identified to be elevated in haematological cancers, are also known tumour-promoting factors. Longitudinal analysis conducted over 3 months showed persistence of several tumour-promoting CCGs in SARS-CoV-2 exposed cancer patients. These data demonstrate a need for increased vigilance for haematological malignancy patients as a part of long COVID follow-up.
The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer
Authors: Gibert-Ramos Albert , Sanfeliu-Redondo David , Aristu-Zabalza Peio , Martínez-Alcocer Ana , Gracia-Sancho Jordi , Guixé-Muntet Sergi , Fernández-Iglesias Anabel
Published: November 2021

The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.
Autophagy: The Potential Link between SARS-CoV-2 and Cancer
Authors: Habibzadeh Parham , Dastsooz Hassan , Eshraghi Mehdi , Łos Marek J. , Klionsky Daniel J. , Ghavami Saeid
Published: November 2021

COVID-19 infection survivors suffer from a constellation of symptoms referred to as post-acute COVID-19 syndrome. However, in the wake of recent evidence highlighting the long-term persistence of SARS-CoV-2 antigens in tissues and emerging information regarding the interaction between SARS-CoV-2 proteins and various components of the host cell macroautophagy/autophagy machinery, the unforeseen long-term consequences of this infection, such as increased risk of malignancies, should be explored. Although SARS-CoV-2 is not considered an oncogenic virus, the possibility of increased risk of cancer among COVID-19 survivors cannot be ruled out. Herein, we provide an overview of the possible mechanisms leading to cancer development, particularly obesity-related cancers (e.g., colorectal cancer), resulting from defects in autophagy and the blockade of the autophagic flux, and also immune escape in COVID-19 survivors. We also highlight the potential long-term implications of COVID-19 infection in the prognosis of patients with cancer and their response to different cancer treatments. Finally, we consider future directions for further investigations on this matter.
Diagnostic Accuracy of Liquid Biopsy in Endometrial Cancer
Authors: Łukasiewicz Marta , Pastuszak Krzysztof , Łapińska-Szumczyk Sylwia , Różański Robert , Veld Sjors G. J. G. In ‘t , Bieńkowski Michał , Stokowy Tomasz , Ratajska Magdalena , Best Myron G. , Würdinger Thomas , Żaczek Anna J. , Supernat Anna , Jassem Jacek
Published: November 2021

Background: Liquid biopsy is a minimally invasive collection of a patient body fluid sample. In oncology, they offer several advantages compared to traditional tissue biopsies. However, the potential of this method in endometrial cancer (EC) remains poorly explored. We studied the utility of tumor educated platelets (TEPs) and circulating tumor DNA (ctDNA) for preoperative EC diagnosis, including histology determination. Methods: TEPs from 295 subjects (53 EC patients, 38 patients with benign gynecologic conditions, and 204 healthy women) were RNA-sequenced. DNA sequencing data were obtained for 519 primary tumor tissues and 16 plasma samples. Artificial intelligence was applied to sample classification. Results: Platelet-dedicated classifier yielded AUC of 97.5% in the test set when discriminating between healthy subjects and cancer patients. However, the discrimination between endometrial cancer and benign gynecologic conditions was more challenging, with AUC of 84.1%. ctDNA-dedicated classifier discriminated primary tumor tissue samples with AUC of 96% and ctDNA blood samples with AUC of 69.8%. Conclusions: Liquid biopsies show potential in EC diagnosis. Both TEPs and ctDNA profiles coupled with artificial intelligence constitute a source of useful information. Further work involving more cases is warranted.
Sustainable Synthesis of Silver Nanoparticles Using Marine Algae for Catalytic Degradation of Methylene Blue
Authors: Somasundaram Chandra Kishore , Atchudan Raji , Edison Thomas Nesakumar Jebakumar Immanuel , Perumal Suguna , Vinodh Rajangam , Sundramoorthy Ashok K. , Babu Rajendran Suresh , Alagan Muthulakshmi , Lee Yong Rok
Published: November 2021

Herein, Sargassum coreanum (marine algae)-mediated silver nanoparticles (AgNPs) were successfully synthesized by a simple reduction method. The synthesized AgNPs were characterized using ultraviolet-visible spectroscopy, attenuated total reflection Fourier transformed infrared spectroscopy, X-ray diffractometry, field emission scanning electron microscopy (FESEM) with energy-dispersive X-ray (EDX) spectroscopy, and high-resolution transmission electron microscopy (HR-TEM) analysis. The acquired colloidal AgNPs were strongly absorbed around 420 nm and displayed brown color under visible light. The XRD pattern of AgNPs exposed their face-centered cubic geometry along with crystalline nature. The HRTEM images of synthesized AgNPs confirmed the mean particle size of 19 nm with a distorted spherical shape, and the calculated interlayer distance (d-spacing value) was about 0.24 nm. Further, the catalytic degradation of methylene blue using sodium borohydride and AgNPs was monitored using UV–vis spectroscopy. The result revealed that AgNPs performed as a superior catalyst, which completely degraded MB in 20 min. The rate constant for MB degradation was calculated to be 0.106 min−1, demonstrating that the marine algae-mediated AgNPs had outstanding catalytic activity. This approach is easy and environmentally benign, which can be applied for environmental-based applications such as dye degradation and pollutant detoxification.
Examination of the Catalytic Role of the Axial Cystine Ligand in the Co-Type Nitrile Hydratase from Pseudonocardia thermophila JCM 3095
Authors: Ogutu Irene R. A. M. , St. Maurice Martin , Bennett Brian , Holz Richard C.
Published: November 2021

The strictly conserved αSer162 residue in the Co-type nitrile hydratase from Pseudonocardia thermophila JCM 3095 (PtNHase), which forms a hydrogen bond to the axial αCys108-S atom, was mutated into an Ala residue. The αSer162Ala yielded two different protein species: one was the apoform (αSerA) that exhibited no observable activity, and the second (αSerB) contained its full complement of cobalt ions and was active with a kcat value of 63 ± 3 s−1 towards acrylonitrile at pH 7.5. The X-ray crystal structure of αSerA was determined at 1.85 Å resolution and contained no detectable cobalt per α2β2 heterotetramer. The axial αCys108 ligand itself was also mutated into Ser, Met, and His ligands. All three of these αCys108 mutant enzymes contained only half of the cobalt complement of wild-type PtNHase, but were able to hydrate acrylonitrile with kcat values of 120 ± 6, 29 ± 3, and 14 ± 1 s−1 for the αCys108His, Ser, and Met mutant enzymes, respectively. As all three of these mutant enzymes are catalytically competent, these data provide the first experimental evidence that transient disulfide bond formation is not catalytically essential for NHases.
Effect of BCG Revaccination on Occupationally Exposed Medical Personnel Vaccinated against SARS-CoV-2
Authors: Ramos-Martinez Espiridión , Falfán-Valencia Ramcés , Pérez-Rubio Gloria , Andrade Warrison Athanasio , Rojas-Serrano Jorge , Ambrocio-Ortiz Enrique , Galicia-Álvarez Dennisse S. , Bárcenas-Montiel Isaac , Velasco-Medina Andrea , Velázquez-Sámano Guillermo
Published: November 2021

The production of specific neutralizing antibodies by individuals is thought to be the best option for reducing the number of patients with severe COVID-19, which is the reason why multiple vaccines are currently being administered worldwide. We aimed to explore the effect of revaccination with BCG, on the response to a subsequent anti-SARS-CoV-2 vaccine, in persons occupationally exposed to COVID-19 patients. Two groups of 30 randomized participants were selected: one group received a BCG revaccination, and the other group received a placebo. Subsequently, both groups were vaccinated against SARS-CoV-2. After each round of vaccination, the serum concentration of Th1/Th2 cytokines was determined. At the end of the protocol, neutralizing antibodies were determined and the HLA-DRB loci were genotyped. The participants from the BCG group and anti-SARS-CoV-2 vaccine group had increased serum cytokine concentrations (i.e., IL-1β, IL-4, IL-6, IL-12p70, IL-13, IL-18, GM-CSF, INF-γ, and TNF-α) and higher neutralizing antibody titers, compared to the group with Placebo–anti-SARS-CoV-2. Twelve HLA-DRB1 alleles were identified in the Placebo–anti-SARS-CoV-2 group, and only nine in the group revaccinated with BCG. The DRB1*04 allele exhibited increased frequency in the Placebo–anti-SARS-CoV-2 group; however, no confounding effects were found with this allele. We conclude that revaccination with BCG synergizes with subsequent vaccination against SARS-CoV-2 in occupationally exposed personnel.
Polarization of Type 1 Macrophages Is Associated with the Severity of Viral Encephalitis Caused by Japanese Encephalitis Virus and Dengue Virus
Authors: Jhan Ming-Kai , Chen Chia-Ling , Shen Ting-Jing , Tseng Po-Chun , Wang Yung-Ting , Satria Rahmat Dani , Yu Chia-Yi , Lin Chiou-Feng
Published: November 2021

Infection with flaviviruses causes mild to severe diseases, including viral hemorrhagic fever, vascular shock syndrome, and viral encephalitis. Several animal models explore the pathogenesis of viral encephalitis, as shown by neuron destruction due to neurotoxicity after viral infection. While neuronal cells are injuries caused by inflammatory cytokine production following microglial/macrophage activation, the blockade of inflammatory cytokines can reduce neurotoxicity to improve the survival rate. This study investigated the involvement of macrophage phenotypes in facilitating CNS inflammation and neurotoxicity during flavivirus infection, including the Japanese encephalitis virus, dengue virus (DENV), and Zika virus. Mice infected with different flaviviruses presented encephalitis-like symptoms, including limbic seizure and paralysis. Histology indicated that brain lesions were identified in the hippocampus and surrounded by mononuclear cells. In those regions, both the infiltrated macrophages and resident microglia were significantly increased. RNA-seq analysis showed the gene profile shifting toward type 1 macrophage (M1) polarization, while M1 markers validated this phenomenon. Pharmacologically blocking C-C chemokine receptor 2 and tumor necrosis factor-α partly retarded DENV-induced M1 polarization. In summary, flavivirus infection, such as JEV and DENV, promoted type 1 macrophage polarization in the brain associated with encephalitic severity.
Bench Research Informed by GWAS Results
Authors: Kondratyev Nikolay V. , Alfimova Margarita V. , Golov Arkadiy K. , Golimbet Vera E.
Published: November 2021

Scientifically interesting as well as practically important phenotypes often belong to the realm of complex traits. To the extent that these traits are hereditary, they are usually ‘highly polygenic’. The study of such traits presents a challenge for researchers, as the complex genetic architecture of such traits makes it nearly impossible to utilise many of the usual methods of reverse genetics, which often focus on specific genes. In recent years, thousands of genome-wide association studies (GWAS) were undertaken to explore the relationships between complex traits and a large number of genetic factors, most of which are characterised by tiny effects. In this review, we aim to familiarise ‘wet biologists’ with approaches for the interpretation of GWAS results, to clarify some issues that may seem counterintuitive and to assess the possibility of using GWAS results in experiments on various complex traits.
NR3C1 Glucocorticoid Receptor Gene Polymorphisms Are Associated with Membranous and IgA Nephropathies
Authors: Pac Michał , Krata Natalia , Moszczuk Barbara , Wyczałkowska-Tomasik Aleksandra , Kaleta Beata , Foroncewicz Bartosz , Rudnicki Witold , Pączek Leszek , Mucha Krzysztof
Published: November 2021

Glomerular diseases (GNs) are responsible for approximately 20% of chronic kidney diseases. Glucocorticoid receptor gene (NR3C1) single nucleotide polymorphisms (SNPs) are implicated in differences in predisposition to autoimmunity and steroid sensitivity. The aim of this study was to evaluate the frequency of the NR3C1 SNPs—rs6198, rs41423247 and rs17209237—in 72 IgA nephropathy (IgAN) and 38 membranous nephropathy (MN) patients compared to 175 healthy controls and to correlate the effectiveness of treatment in IgAN and MN groups defined as a reduction of proteinuria <1 g/24 h after 12 months of treatment. Real-time polymerase chain reactions and SNP array-based typing were used. We found significant rs41423247 association with MN (p = 0.026); a significant association of rs17209237 with eGFR reduction after follow-up period in all patients with GNs (p = 0.021) and with the degree of proteinuria after 1 year of therapy in all patients with a glomerulopathy (p = 0.013) and IgAN (p = 0.021); and in the same groups treated with steroids (p = 0.021; p = 0.012). We also observed the association between rs41423247 and IgAN histopathologic findings (p = 0.012). In conclusion, our results indicate that NR3C1 polymorphisms may influence treatment susceptibility and clinical outcome in IgAN and MN.
Immunological Characterization of HIV and SARS-CoV-2 Coinfected Young Individuals
Authors: Vanetti Claudia , Trabattoni Daria , Stracuzzi Marta , Amendola Antonella , Fappani Clara , Rubinacci Valeria , Fenizia Claudio , Gianolio Laura , Biasin Mara , Dighera Anna , Saulle Irma , Tanzi Elisabetta , Zuccotti Gianvincenzo , Clerici Mario , Giacomet Vania
Published: November 2021

While the risk of SARS-CoV-2 infection and/or COVID-19 disease progression in the general population has been largely assessed, its impact on HIV-positive individuals remains unclear. We present clinical and immunological data collected in a cohort of HIV-infected young individuals during the first wave of COVID-19 pandemic. SARS-CoV-2 RNA, virus-specific antibodies, as well as the expression of factors involved in the anti-viral immune response were analyzed. Moreover, we set up an in vitro coinfection assay to study the mechanisms correlated to the coinfection process. Our results did not show any increased risk of severe COVID-19 in HIV-positive young individuals. In those subjects who contracted SARS-CoV-2 infection, an increase in IL-10 expression and production was observed. Furthermore, in the in vitro coinfection assay, we revealed a reduction in SARS-CoV-2 replication associated to an upregulation of IL-10. We speculate that IL-10 could play a crucial role in the course of SARS-CoV-2 infection in HIV-positive individuals. These results might help defining clinical management of HIV/SARS-CoV-2 co-infected young individuals, or putative indications for vaccination schedules in this population.
Macrophage Reprogramming and Cancer Therapeutics: Role of iNOS-Derived NO
Authors: Kashfi Khosrow , Kannikal Jasmine , Nath Niharika
Published: November 2021

Nitric oxide and its production by iNOS is an established mechanism critical to tumor promotion or suppression. Macrophages have important roles in immunity, development, and progression of cancer and have a controversial role in pro- and antitumoral effects. The tumor microenvironment consists of tumor-associated macrophages (TAM), among other cell types that influence the fate of the growing tumor. Depending on the microenvironment and various cues, macrophages polarize into a continuum represented by the M1-like pro-inflammatory phenotype or the anti-inflammatory M2-like phenotype; these two are predominant, while there are subsets and intermediates. Manipulating their plasticity through programming or reprogramming of M2-like to M1-like phenotypes presents the opportunity to maximize tumoricidal defenses. The dual role of iNOS-derived NO also influences TAM activity by repolarization to tumoricidal M1-type phenotype. Regulatory pathways and immunomodulation achieve this through miRNA that may inhibit the immunosuppressive tumor microenvironment. This review summarizes the classical physiology of macrophages and polarization, iNOS activities, and evidence towards TAM reprogramming with current information in glioblastoma and melanoma models, and the immunomodulatory and therapeutic options using iNOS or NO-dependent strategies.
Structural and Optical Properties of CuO Thin Films Synthesized Using Spray Pyrolysis Method
Authors: Diachenko Oleksii , Kováč Jaroslav , Dobrozhan Oleksandr , Novák Patrik , Kováč Jaroslav , Skriniarova Jaroslava , Opanasyuk Anatoliy
Published: November 2021

Copper oxide thin films were obtained using pulsating spray pyrolysis method. The morphological, structural, and optical properties of fabricated films were studied. X-ray analysis revealed that the CuO thin films are single-phase. The study of films morphology by SEM and AFM methods showed that the obtained films have a fairly high surface roughness and contain grains of different shapes and sizes. It was found that the obtained films of copper oxide have high values of the absorption coefficient, which confirms the possibility of their use as absorbing layers for solar cells. The obtained values of the optical band gap of the material are in the range from 1.45 eV to 1.60 eV. Raman spectroscopy revealed three modes A1g, B1g, and B2g, of the crystal structure of monoclinic CuO. The devices based on p-type copper oxide are promising for solar cells fabrication because they can reduce production costs, due to their low cost and inexpensive production methods compared to silicon solar cells fabrication.
Elastic Flexibility in an Optically Active Naphthalidenimine-Based Single Crystal
Authors: Feiler Torvid , Michalchuk Adam A. L. , Schröder Vincent , List-Kratochvil Emil , Emmerling Franziska , Bhattacharya Biswajit
Published: November 2021

Organic single crystals that combine mechanical flexibility and optical properties are important for developing flexible optical devices, but examples of such crystals remain scarce. Both mechanical flexibility and optical activity depend on the underlying crystal packing and the nature of the intermolecular interactions present in the solid state. Hence, both properties can be expected to be tunable by small chemical modifications to the organic molecule. By incorporating a chlorine atom, a reportedly mechanically flexible crystal of (E)-1-(4-bromo-phenyl)iminomethyl-2-hydroxyl-naphthalene (BPIN) produces (E)-1-(4-bromo-2-chloro-phenyl)iminomethyl-2-hydroxyl-naphthalene (BCPIN). BCPIN crystals show elastic bending similar to BPIN upon mechanical stress, but exhibit a remarkable difference in their optical properties as a result of the chemical modification to the backbone of the organic molecule. This work thus demonstrates that the optical properties and mechanical flexibility of molecular materials can, in principle, be tuned independently.
Association of Melanoma-Risk Variants with Primary Melanoma Tumor Prognostic Characteristics and Melanoma-Specific Survival in the GEM Study
Authors: Davari Danielle R. , Orlow Irene , Kanetsky Peter A. , Luo Li , Busam Klaus J. , Sharma Ajay , Kricker Anne , Cust Anne E. , Anton-Culver Hoda , Gruber Stephen B. , Gallagher Richard P. , Zanetti Roberto , Rosso Stefano , Sacchetto Lidia , Dwyer Terence , Gibbs David C. , Ollila David W. , Begg Colin B. , Berwick Marianne , Thomas Nancy E.
Published: November 2021

Genome-wide association studies (GWAS) and candidate pathway studies have identified low-penetrant genetic variants associated with cutaneous melanoma. We investigated the association of melanoma-risk variants with primary melanoma tumor prognostic characteristics and melanoma-specific survival. The Genes, Environment, and Melanoma Study enrolled 3285 European origin participants with incident invasive primary melanoma. For each of 47 melanoma-risk single nucleotide polymorphisms (SNPs), we used linear and logistic regression modeling to estimate, respectively, the per allele mean changes in log of Breslow thickness and odds ratios for presence of ulceration, mitoses, and tumor-infiltrating lymphocytes (TILs). We also used Cox proportional hazards regression modeling to estimate the per allele hazard ratios for melanoma-specific survival. Passing the false discovery threshold (p = 0.0026) were associations of IRF4 rs12203592 and CCND1 rs1485993 with log of Breslow thickness, and association of TERT rs2242652 with presence of mitoses. IRF4 rs12203592 also had nominal associations (p < 0.05) with presence of mitoses and melanoma-specific survival, as well as a borderline association (p = 0.07) with ulceration. CCND1 rs1485993 also had a borderline association with presence of mitoses (p = 0.06). MX2 rs45430 had nominal associations with log of Breslow thickness, presence of mitoses, and melanoma-specific survival. Our study indicates that further research investigating the associations of these genetic variants with underlying biologic pathways related to tumor progression is warranted.
Epithelial-Myoepithelial Carcinoma of the Minor Salivary Glands: Case Series with Comprehensive Review
Authors: Okuyama Kohei , Michi Yasuyuki , Kashima Yoshihisa , Tomioka Hirofumi , Hirai Hideaki , Yokokawa Misaki , Yamagata Yuko , Kuroshima Takeshi , Sato Yuriko , Tsuchiya Maiko , Kayamori Kou , Ikeda Tohru , Harada Hiroyuki
Published: November 2021

Epithelial-myoepithelial carcinoma (EMC) is a rare salivary gland tumor that is histologically characterized by biphasic tubular structures composed of inner ductal and outer clear myoepithelial cells, which is especially uncommon in the minor salivary glands (MSG). Because of its histologic variety, complexity, and heterogeneity, it is sometimes challenging to make the accurate diagnosis. Here, we report a literature review of EMC of the MSGs with our experience of two cases. Incisional biopsy was suggestive of pleomorphic adenoma in Case 1 and pleomorphic adenoma or a low-grade salivary gland carcinoma in Case 2. Both cases were performed intraoral tumor resection, and they have good postoperative courses and are alive with no evidence of local recurrence or metastasis at 31 and 16 months, respectively. Considering that the anatomy, structure, and size of salivary glands are quite different from MSGs, it might be difficult to predict EMCs of the MSG similarly to EMCs of the major salivary glands. This comprehensive review also reports the features of EMC of the MSG cases and the trends of diagnosis and discusses treatment strategy.
Postmenopausal Chinese-Singaporean Women Have a Higher Ratio of Visceral to Subcutaneous Adipose Tissue Volume than Caucasian Women of the Same Age and BMI
Authors: Kalimeri Maria , Totman John J. , Baum Thomas , Diefenbach Maximilian N. , Hauner Hans , Makowski Marcus R. , Subburaj Karupppasamy , Cameron-Smith David , Henry Christiani Jeyakumar , Karampinos Dimitrios C. , Junker Daniela
Published: November 2021

Central fat accumulation is a significant determinant of cardio-metabolic health risk, known to differ between ethnically distinct human populations. Despite evidence for preferential central adiposity in Asian populations, the proportional distribution between the subcutaneous and visceral compartments in Chinese postmenopausal women has not been thoroughly investigated. For this analysis, volumetrically quantified subcutaneous and visceral adipose tissue (SAT, VAT) in the pelvic and abdominal regions of postmenopausal Asian (Chinese-Singaporean) and Caucasian (German) women matched for age and Body Mass Index (BMI) was undertaken, to examine such differences between the two groups. Volumes were calculated from segmentations of magnetic resonance imaging datasets of the abdomen and pelvis. Despite SAT, VAT, and the corresponding total adipose tissue (TAT) being similar between the groups, VAT/SAT and VAT/TAT were higher in the Asian group (by 24.5% and 18.2%, respectively, each p = 0.02). Further, VAT/SAT and VAT/TAT were positively correlated with BMI in the Caucasian group only (p = 0.02 and p = 0.01, respectively). We concluded that VAT is proportionally higher in the non-obese Asian women, compared to the Caucasian women of matched age and BMI. This conclusion is in agreement with existing literature showing higher abdominal adiposity in Asian populations. Additionally, in the Asian group, BMI did not correlate with visceral adiposity on a significant level. Further analysis is required to examine the extent to which this increased VAT may impact cardio-metabolic health. There is, however, a need to emphasize healthy lifestyle behaviors in non-obese post-menopausal women of Chinese ancestry.
New Parameterized Inequalities for η-Quasiconvex Functions via (p, q)-Calculus
Authors: Kalsoom Humaira , Vivas-Cortez Miguel , Idrees Muhammad , Agarwal Praveen
Published: November 2021

In this work, first, we consider novel parameterized identities for the left and right part of the (p,q)-analogue of Hermite–Hadamard inequality. Second, using these new parameterized identities, we give new parameterized (p,q)-trapezoid and parameterized (p,q)-midpoint type integral inequalities via η-quasiconvex function. By changing values of parameter μ∈[0,1], some new special cases from the main results are obtained and some known results are recaptured as well. Finally, at the end, an application to special means is given as well. This new research has the potential to establish new boundaries in comparative literature and some well-known implications. From an application perspective, the proposed research on the η-quasiconvex function has interesting results that illustrate the applicability and superiority of the results obtained.
On the Problem of Small Objects
Authors: Brown Daniel G. , Mondol Tiasa
Published: November 2021

We discuss how to assess computationally the aesthetic value of “small” objects, namely those that have short digital descriptions. Such small objects still matter: they include headlines, poems, song lyrics, short musical scripts and other culturally crucial items. Yet, small objects are a confounding case for our recent work adapting ideas from algorithmic information theory (AIT) to the domain of computational creativity, as they cannot be either logically deep or sophisticated following the traditional definitions of AIT. We show how restricting the class of models under analysis can make it the case that we can still separate high-quality small objects from ordinary ones, and discuss the strengths and limitations of our adaptation.
Perceptions of University Students towards Digital Transformation during the Pandemic
Authors: Hervás-Gómez Carlos , Díaz-Noguera María Dolores , De la Calle-Cabrera Ana María , Guijarro-Cordobés Olga
Published: November 2021

The aim of this study is to determine the perceptions of university students toward teaching–learning processes during the COVID-19 pandemic. This research gathers inquiries made worldwide on the perceptions of students in higher education during a state of alarm. The proposed objectives were (a) to analyse the perception of students toward teaching–learning processes in university; (b) to determine the assessment given by students about the changes that took place in university teaching as a result of COVID-19; and (c) to explore resources (hardware and software), professional collaboration, digital pedagogy and student empowerment (motivation) regarding digital education and recent changes in university teaching due to the pandemic. This study used a non-experimental, descriptive design based on opinion polls or surveys. The results show a positive correlation between digital pedagogy, student motivation and digital environments. As a conclusion, we encourage the scientific community to continue delving into the motivation, collaboration and reflective exchange of experiences, self-learning and promotion of initiatives that foster the development of competencies in future teachers. It is also important to continue the research on integrated designs in training processes in university, tutoring and continuous evaluation, as they are key for digital transformation in universities.
Using School-Level Data to Investigate the Impact of a One-to-One Mathematics Teaching Resource in English Primary Schools
Authors: Rolph Chris
Published: November 2021

This research investigates the potential for a one-to-one coaching tool used by adults other than teachers to be able to deliver greater mathematics progress for primary school children without adding significantly to school costs. Plus 1 and Power of 2 (+1 and Po2) are workbooks designed to be used by adults other than teachers working on a one-to-one basis with children to develop numeracy skills. This quantitative study seeks to examine the impact of +1 and Po2 by considering performance data aggregated at the school level. The attainment of children at 1071 English schools which use the +1 and Po2 products was compared with that of peers in other schools using a quasi-experimental research design based on England’s national performance measures. Statistical analysis suggests that schools using +1 and Po2 show higher levels of mathematics attainment than those who may have used other resources. Furthermore, there is an important finding that assessment attendance is higher, and disapplication from the curriculum lower, in schools using +1 and Po2. This indicates that use of this one-to-one intervention improves access to national tests for children and represents an opportunity for school leaders to maximise the cost effectiveness of existing non-teaching staff or volunteers.
Peak Shaving with Battery Energy Storage Systems in Distribution Grids: A Novel Approach to Reduce Local and Global Peak Loads
Authors: Kucevic Daniel , Semmelmann Leo , Collath Nils , Jossen Andreas , Hesse Holger
Published: November 2021

The growing global electricity demand and the upcoming integration of charging options for electric vehicles is creating challenges for power grids, such as line over loading. With continuously falling costs for lithium-ion batteries, storage systems represent an alternative to conventional grid reinforcement. This paper proposes an operation strategy for battery energy storage systems, targeted at industrial consumers to achieve both an improvement in the distribution grid and electricity bill savings for the industrial consumer. The objective is to reduce the peak power at the point of common coupling in existing distribution grids by adapting the control of the battery energy storage system at individual industrial consumer sites. An open-source simulation tool, which enables a realistic simulation of the effects of storage systems in different operating modes on the distribution grid, has been adapted as part of this work. Further information on the additional stress on the storage system is derived from a detailed analysis based on six key characteristics. The results show that, with the combined approach, both the local peak load and the global peak load can be reduced, while the stress on the energy storage is not significantly increased. The peak load at the point of common coupling is reduced by 5.6 kVA to 56.7 kVA and the additional stress for the storage system is, on average, for a six month simulation, period only 1.2 full equivalent cycles higher.