bluuebunny/crossref_metadata_2025 huggingface dataset:
Topical Capsaicin in Poly(lactic-co-glycolic)acid (PLGA) Nanoparticles Decreases Acute Itch and Heat Pain
Authors: Malewicz Nathalie M. , Rattray Zahra , Oeck Sebastian , Jung Sebastian , Escamilla-Rivera Vicente , Chen Zeming , Tang Xiangjun , Zhou Jiangbing , LaMotte Robert H.
Published: May 2022

Background: Capsaicin, the hot pepper agent, produces burning followed by desensitization. To treat localized itch or pain with minimal burning, low capsaicin concentrations can be repeatedly applied. We hypothesized that alternatively controlled release of capsaicin from poly(lactic-co-glycolic acid) (PLGA) nanoparticles desensitizes superficially terminating nociceptors, reducing burning. Methods: Capsaicin-loaded PLGA nanoparticles were prepared (single-emulsion solvent evaporation) and characterized (size, morphology, capsaicin loading, encapsulation efficiency, in vitro release profile). Capsaicin-PLGA nanoparticles were applied to murine skin and evaluated in healthy human participants (n = 21) for 4 days under blinded conditions, and itch and nociceptive sensations evoked by mechanical, heat stimuli and pruritogens cowhage, β-alanine, BAM8-22 and histamine were evaluated. Results: Nanoparticles (loading: 58 µg capsaicin/mg) released in vitro 23% capsaicin within the first hour and had complete release at 72 h. In mice, 24 h post-application Capsaicin-PLGA nanoparticles penetrated the dermis and led to decreased nociceptive behavioral responses to heat and mechanical stimulation (desensitization). Application in humans produced a weak to moderate burning, dissipating after 3 h. A loss of heat pain up to 2 weeks was observed. After capsaicin nanoparticles, itch and nociceptive sensations were reduced in response to pruritogens cowhage, β-alanine or BAM8-22, but were normal to histamine. Conclusions: Capsaicin nanoparticles could be useful in reducing pain and itch associated with pruritic diseases that are histamine-independent.
Plant Alkaloid Tetrandrine Is a Nuclear Receptor 4A1 Antagonist and Inhibits Panc-1 Cell Growth In Vitro and In Vivo
Authors: Lee Hyo-Seon , Kim Dae Hwan , Lee In-Seon , Park Ji-Hyun , Martin Gregory , Safe Stephen , Kim Keuk-Jun , Kim Joung-Hee , Jang Byung Ik , Lee Syng-Ook
Published: May 2022

The orphan nuclear receptor 4A1 (NR4A1) is highly expressed in human pancreatic cancer cells and exerts pro-oncogenic activity. In a previous study, we demonstrated that fangchinoline (FCN), a natural inhibitor of nuclear NR4A1, induces NR4A1-dependent apoptosis in human pancreatic cancer cells. In this study, we evaluated FCN and its structural analogs (berbamine, isotetrandrine, tetrandrine, and tubocurarine) for their inhibitory effects on NR4A1 transactivity, and confirmed that tetrandrine (TTD) showed the highest inhibitory effect in pancreatic cancer cells. Moreover, in a tryptophan fluorescence quenching assay, TTD directly bound to the ligand binding domain (LBD) of NR4A1 with a KD value of 10.60 μM. Treatment with TTD decreased proliferation and induced apoptosis in Panc-1 human pancreatic cancer cells in part through the reduced expression of the Sp1-dependent anti-apoptotic gene survivin and induction of ROS-mediated endoplasmic reticulum stress, which are the well-known NR4A1-dependent proapoptotic pathways. Furthermore, at a dose of 25 mg/kg/day, TTD reduced tumor growth in an athymic nude mouse xenograft model bearing Panc-1 cells. These data show that TTD is an NR4A1 antagonist and that modulation of the NR4A1-mediated pro-survival pathways is involved in the antitumor effects of TTD.
Role of Vitamin K in Chronic Kidney Disease: A Focus on Bone and Cardiovascular Health
Authors: Bellone Federica , Cinquegrani Maria , Nicotera Ramona , Carullo Nazareno , Casarella Alessandro , Presta Pierangela , Andreucci Michele , Squadrito Giovanni , Mandraffino Giuseppe , Prunestì Marcello , Vocca Cristina , De Sarro Giovambattista , Bolignano Davide , Coppolino Giuseppe
Published: May 2022

Chronic kidney disease (CKD) is commonly associated with vitamin K deficiency. Some of the serious complications of CKD are represented by cardiovascular disease (CVD) and skeletal fragility with an increased risk of morbidity and mortality. A complex pathogenetic link between hormonal and ionic disturbances, bone tissue and metabolism alterations, and vascular calcification (VC) exists and has been defined as chronic kidney disease–mineral and bone disorder (CKD-MBD). Poor vitamin K status seems to have a key role in the progression of CKD, but also in the onset and advance of both bone and cardiovascular complications. Three forms of vitamin K are currently known: vitamin K1 (phylloquinone), vitamin K2 (menaquinone), and vitamin K3 (menadione). Vitamin K plays different roles, including in activating vitamin K-dependent proteins (VKDPs) and in modulating bone metabolism and contributing to the inhibition of VC. This review focuses on the biochemical and functional characteristics of vitamin K vitamers, suggesting this nutrient as a possible marker of kidney, CV, and bone damage in the CKD population and exploring its potential use for promoting health in this clinical setting. Treatment strategies for CKD-associated osteoporosis and CV disease should include vitamin K supplementation. However, further randomized clinical studies are needed to assess the safety and the adequate dosage to prevent these CKD complications.
The Role of Nuclear Factor Kappa B (NF-κB) in Development and Treatment of COVID-19: Review
Authors: Gudowska-Sawczuk Monika , Mroczko Barbara
Published: May 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 19 (COVID-19), a disease that has affected more than 500 million people worldwide since the end of 2019. Due to its high complications and death rates, there is still a need to find the best therapy for SARS-CoV-2 infection. The dysregulation of the inflammatory response in COVID-19 plays a very important role in disease progression. It has been observed that abnormal activity of Nuclear Factor kappa B (NF-κB) is directly associated with, inter alia, increased synthesis of proinflammatory factors. Therefore, this review paper focuses on the functions of NF-κB in the development of SARS-CoV-2 infection and potential application of NF-κB inhibitors in COVID-19 immunotherapy. A comprehensive literature search was performed using the MEDLINE/PubMed database. In the current review, it is highlighted that NF-κB plays important functions in the modulation of an adaptive inflammatory response, including inducing the expression of proinflammatory genes. Increased activation of NF-κB in SARS-CoV-2 infection was observed. The association between NF-κB activation and the expression of SARS-CoV-2 structural and non-structural proteins were also reported. It was observed that modulation of NF-κB using, e.g., traditional Chinese medicine or glucocorticosteroids resulted in decreased synthesis of proinflammatory factors caused by SARS-CoV-2 infection. This review summarizes the role of NF-κB in COVID-19 and describes its potential immunotherapeutic target in treatment of SARS-CoV-2 infection. However, indisputably more studies involving patients with a severe course of COVID-19 are sorely needed.
Beyond Photoprotection: The Multifarious Roles of Flavonoids in Plant Terrestrialization
Authors: Nascimento Luana Beatriz dos Santos , Tattini Massimiliano
Published: May 2022

Plants evolved an impressive arsenal of multifunctional specialized metabolites to cope with the novel environmental pressures imposed by the terrestrial habitat when moving from water. Here we examine the multifarious roles of flavonoids in plant terrestrialization. We reason on the environmental drivers, other than the increase in UV-B radiation, that were mostly responsible for the rise of flavonoid metabolism and how flavonoids helped plants in land conquest. We are reasonably based on a nutrient-deficiency hypothesis for the replacement of mycosporine-like amino acids, typical of streptophytic algae, with the flavonoid metabolism during the water-to-land transition. We suggest that flavonoids modulated auxin transport and signaling and promoted the symbiosis between plants and fungi (e.g., arbuscular mycorrhizal, AM), a central event for the conquest of land by plants. AM improved the ability of early plants to take up nutrients and water from highly impoverished soils. We offer evidence that flavonoids equipped early land plants with highly versatile “defense compounds”, essential for the new set of abiotic and biotic stressors imposed by the terrestrial environment. We conclude that flavonoids have been multifunctional since the appearance of plants on land, not only acting as UV filters but especially improving both nutrient acquisition and biotic stress defense.
Molecular Research on Oral Diseases and Related Biomaterials: A Journey from Oral Cell Models to Advanced Regenerative Perspectives
Authors: Steinberg Thorsten , Dieterle Martin Philipp , Tomakidi Pascal
Published: May 2022

Oral diseases such as gingivitis, periodontitis, and oral cancer affect millions of people worldwide. Much research has been conducted to understand the pathogenetic mechanisms of these diseases and translate this knowledge into therapeutics. This review aims to take the reader on a journey from the initial molecular discoveries to complex regenerative issues in oral medicine. For this, a semi-systematic literature search was carried out in Medline and Web of Science databases to retrieve the primary literature describing oral cell models and biomaterial applications in oral regenerative medicine. First, an in vitro cell model of gingival keratinocytes is discussed, which illustrates patho- and physiologic principles in the context of oral epithelial homeostasis and carcinogenesis and represents a cellular tool to understand biomaterial-based approaches for periodontal tissue regeneration. Consequently, a layered gradient nonwoven (LGN) is described, which demonstrates that the key features of biomaterials serve as candidates for oral tissue regeneration. LGN supports proper tissue formation and obeys the important principles for molecular mechanotransduction. Furthermore, current biomaterial-based tissue regeneration trends, including polymer modifications, cell-based treatments, antimicrobial peptides and optogenetics, are introduced to represent the full spectrum of current approaches to oral disease mitigation and prevention. Altogether, this review is a foray through established and new concepts in oral regenerative medicine and illustrates the process of knowledge translation from basic molecular and cell biological research to future clinical applications.
Loss of SP-A in the Lung Exacerbates Pulmonary Fibrosis
Authors: Kim Kyunghwa , Shin Dasom , Lee Gaheon , Bae Hyunsu
Published: May 2022

Idiopathic pulmonary fibrosis (IPF) is a devastating and common chronic lung disease that is pathologically characterized by the destruction of lung architecture and the accumulation of extracellular matrix in the lung. Previous studies have shown an association between lung surfactant protein (SP) and the pathogenesis of IPF, as demonstrated by mutations and the altered expression of SP in patients with IPF. However, the role of SP in the development of lung fibrosis is poorly understood. In this study, the role of surfactant protein A (SP-A) was explored in experimental lung fibrosis induced with a low or high dose of bleomycin (BLM) and CRISPR/Cas9-mediated genetic deletion of SP-A. Our results showed that lung SP-A deficiency in mice promoted the development of fibrotic damage and exacerbated inflammatory responses to the BLM challenge. In vitro experiments with murine lung epithelial LA-4 cells demonstrated that in response to transforming growth factor-β1 (TGF-β1), LA-4 cells had a decreased protein expression of SP-A. Furthermore, exogenous SP administration to LA-4 cells inhibited the TGF-β1-induced upregulation of fibrotic markers. Overall, these findings suggest a novel antifibrotic mechanism of SP-A in the development of lung fibrosis, which indicates the therapeutic potential of the lung SP-A in preventing the development of IPF.
Cloning and Functional Analysis of TaWRI1Ls, the Key Genes for Grain Fatty Acid Synthesis in Bread Wheat
Authors: Yang Fengping , Liu Guoyu , Wu Ziyan , Zhang Dongxue , Zhang Yufeng , You Mingshan , Li Baoyun , Zhang Xiuhai , Liang Rongqi
Published: May 2022

WRINKLED1 (WRI1), an APETALA2 (AP2) transcription factor (TF), critically regulates the processes related to fatty acid synthesis, storage oil accumulation, and seed development in plants. However, the WRI1 genes remain unknown in allohexaploid bread wheat (Triticum aestivum L.). In this study, based on the sequence of Arabidopsis AtWRI1, two TaWRI1Ls genes of bread wheat, TaWRI1L1 and TaWRI1L2, were cloned. TaWRI1L2 was closely related to monocotyledons and clustered in one subgroup with AtWRI1, while TaWRI1L1 was clustered in another subgroup with AtWRI3 and AtWRI4. Both were expressed highly in the developmental grain, subcellular localized in the nucleus, and showed transcriptional activation activity. TaWRI1L2, rather than TaWRI1L1, promoted oil body accumulation and significantly increased triglyceride (TAG) content in tobacco leaves. Overexpression of TaWRI1L2 compensated for the functional loss of AtWRI1 in an Arabidopsis mutant and restored the wild-type phenotypes of seed shape, generation, and fatty acid synthesis and accumulation. Knockout of TaWRI1L2 reduced grain size, 1000 grain weight, and grain fatty acid synthesis in bread wheat. Conclusively, TaWRI1L2, rather than TaWRI1L1, was the key transcriptional factor in the regulation of grain fatty acid synthesis in bread wheat. This study lays a foundation for gene regulation and genetic manipulation of fatty acid synthesis in wheat genetic breeding programs.
Innovation through Tradition: The Current Challenges in Cancer Treatment
Authors: Sapio Luigi , Naviglio Silvio
Published: May 2022

Despite the huge efforts in identifying novel risk factors, earlier diagnostic markers and alternative therapeutic approaches, malignant disorders continue to pose the second leading cause of death worldwide [...]
Correction: Rondinone et al. Extensive Placental Methylation Profiling in Normal Pregnancies. Int. J. Mol. Sci. 2021, 22, 2136
Authors: Rondinone Ornella , Murgia Alessio , Costanza Jole , Tabano Silvia , Camanni Margherita , Corsaro Luigi , Fontana Laura , Colapietro Patrizia , Calzari Luciano , Motta Silvia , Santaniello Carlo , Radaelli Tatjana , Ferrazzi Enrico , Bosari Silvano , Gentilini Davide , Sirchia Silvia , Miozzo Monica
Published: May 2022

In the original publication [...]
Glucosylceramide Changes Bacterial Metabolism and Increases Gram-Positive Bacteria through Tolerance to Secondary Bile Acids In Vitro
Authors: Dai Huanghuang , Otsuka Akira , Tanabe Kurumi , Yanagita Teruyoshi , Nakayama Jiro , Kitagaki Hiroshi
Published: May 2022

Glucosylceramide is present in many foods, such as crops and fermented foods. Most glucosylceramides are not degraded or absorbed in the small intestine and pass through the large intestine. Glucosylceramide exerts versatile effects on colon tumorigenesis, skin moisture, cholesterol metabolism and improvement of intestinal microbes in vivo. However, the mechanism of action has not yet been fully elucidated. To gain insight into the effect of glucosylceramide on intestinal microbes, glucosylceramide was anaerobically incubated with the dominant intestinal microbe, Blautia coccoides, and model intestinal microbes. The metabolites of the cultured broth supplemented with glucosylceramide were significantly different from those of broth not treated with glucosylceramide. The number of Gram-positive bacteria was significantly increased upon the addition of glucosylceramide compared to that in the control. Glucosylceramide endows intestinal microbes with tolerance to secondary bile acid. These results first demonstrated that glucosylceramide plays a role in the modification of intestinal microbes.
Genetic Dissection of Light-Regulated Adventitious Root Induction in Arabidopsis thaliana Hypocotyls
Authors: Zeng Yinwei , Schotte Sebastien , Trinh Hoang Khai , Verstraeten Inge , Li Jing , Van de Velde Ellen , Vanneste Steffen , Geelen Danny
Published: May 2022

Photomorphogenic responses of etiolated seedlings include the inhibition of hypocotyl elongation and opening of the apical hook. In addition, dark-grown seedlings respond to light by the formation of adventitious roots (AR) on the hypocotyl. How light signaling controls adventitious rooting is less well understood. Hereto, we analyzed adventitious rooting under different light conditions in wild type and photomorphogenesis mutants in Arabidopsis thaliana. Etiolation was not essential for AR formation but raised the competence to form AR under white and blue light. The blue light receptors CRY1 and PHOT1/PHOT2 are key elements contributing to the induction of AR formation in response to light. Furthermore, etiolation-controlled competence for AR formation depended on the COP9 signalosome, E3 ubiquitin ligase CONSTITUTIVELY PHOTOMORPHOGENIC (COP1), the COP1 interacting SUPPRESSOR OF PHYA-105 (SPA) kinase family members (SPA1,2 and 3) and Phytochrome-Interacting Factors (PIF). In contrast, ELONGATED HYPOCOTYL5 (HY5), suppressed AR formation. These findings provide a genetic framework that explains the high and low AR competence of Arabidopsis thaliana hypocotyls that were treated with dark, and light, respectively. We propose that light-induced auxin signal dissipation generates a transient auxin maximum that explains AR induction by a dark to light switch.
Circulating Monocyte Subsets and Transcatheter Aortic Valve Replacement
Authors: Lassalle Fanny , Rosa Mickael , Staels Bart , Van Belle Eric , Susen Sophie , Dupont Annabelle
Published: May 2022

Transcatheter aortic valve replacement (TAVR), as an alternative to open heart surgery, has revolutionized the treatment of severe aortic valve stenosis (AVS), the most common valvular disorder in the elderly. AVS is now considered a form of atherosclerosis and, like the latter, partly of inflammatory origin. Patients with high-grade AVS have a highly disturbed blood flow associated with high levels of shear stress. The immediate reopening of the valve during TAVR leads to a sudden restoration of a normal blood flow hemodynamic. Despite its good prognosis for patients, TAVR remains associated with bleeding or thrombotic postprocedural complications, involving mechanisms that are still poorly understood. Many studies report the close link between blood coagulation and inflammation, termed thromboinflammation, including monocytes as a major actor. The TAVR procedure represents a unique opportunity to study the influence of shear stress on human monocytes, key mediators of inflammation and hemostasis processes. The purpose of this study was to conduct a review of the literature to provide a comprehensive overview of the impact of TAVR on monocyte phenotype and subset repartition and the association of these parameters with the clinical outcomes of patients with severe AVS who underwent TAVR.
The Mechanisms of Thin Filament Assembly and Length Regulation in Muscles
Authors: Szikora Szilárd , Görög Péter , Mihály József
Published: May 2022

The actin containing tropomyosin and troponin decorated thin filaments form one of the crucial components of the contractile apparatus in muscles. The thin filaments are organized into densely packed lattices interdigitated with myosin-based thick filaments. The crossbridge interactions between these myofilaments drive muscle contraction, and the degree of myofilament overlap is a key factor of contractile force determination. As such, the optimal length of the thin filaments is critical for efficient activity, therefore, this parameter is precisely controlled according to the workload of a given muscle. Thin filament length is thought to be regulated by two major, but only partially understood mechanisms: it is set by (i) factors that mediate the assembly of filaments from monomers and catalyze their elongation, and (ii) by factors that specify their length and uniformity. Mutations affecting these factors can alter the length of thin filaments, and in human cases, many of them are linked to debilitating diseases such as nemaline myopathy and dilated cardiomyopathy.
Recent Advances in Intermediate Filaments—Volume 1
Authors: Saez Angela , Gonzalez-Granado Jose M.
Published: May 2022

We would like to make readers of the second edition of the Special Issue from the International Journal of Molecular Sciences on the Recent Advances in Intermediate Filaments aware of the content of the first edition on this same topic [...]
AtERF71/HRE2, an Arabidopsis AP2/ERF Transcription Factor Gene, Contains Both Positive and Negative Cis-Regulatory Elements in Its Promoter Region Involved in Hypoxia and Salt Stress Responses
Authors: Seok Hye-Yeon , Tran Huong Thi , Lee Sun-Young , Moon Yong-Hwan
Published: May 2022

In the signal transduction network, from the perception of stress signals to stress-responsive gene expression, various transcription factors and cis-regulatory elements in stress-responsive promoters coordinate plant adaptation to abiotic stresses. Among the AP2/ERF transcription factor family, group VII ERF (ERF-VII) genes, such as RAP2.12, RAP2.2, RAP2.3, AtERF73/HRE1, and AtERF71/HRE2, are known to be involved in the response to hypoxia in Arabidopsis. Notably, HRE2 has been reported to be involved in responses to hypoxia and osmotic stress. In this study, we dissected HRE2 promoter to identify hypoxia- and salt stress-responsive region(s). The analysis of the promoter deletion series of HRE2 using firefly luciferase and GUS as reporter genes indicated that the −116 to −2 region is responsible for both hypoxia and salt stress responses. Using yeast one-hybrid screening, we isolated HAT22/ABIG1, a member of the HD-Zip II subfamily, which binds to the −116 to −2 region of HRE2 promoter. Interestingly, HAT22/ABIG1 repressed the transcription of HRE2 via the EAR motif located in the N-terminal region of HAT22/ABIG1. HAT22/ABIG1 bound to the 5′-AATGATA-3′ sequence, HD-Zip II-binding-like cis-regulatory element, in the −116 to −2 region of HRE2 promoter. Our findings demonstrate that the −116 to −2 region of HRE2 promoter contains both positive and negative cis-regulatory elements, which may regulate the expression of HRE2 in responses to hypoxia and salt stress and that HAT22/ABIG1 negatively regulates HRE2 transcription by binding to the HD-Zip II-binding-like element in the promoter region.
RNA Interference: Promising Approach to Combat Plant Viruses
Authors: Akbar Sehrish , Wei Yao , Zhang Mu-Qing
Published: May 2022

Plant viruses are devastating plant pathogens that severely affect crop yield and quality. Plants have developed multiple lines of defense systems to combat viral infection. Gene silencing/RNA interference is the key defense system in plants that inhibits the virulence and multiplication of pathogens. The general mechanism of RNAi involves (i) the transcription and cleavage of dsRNA into small RNA molecules, such as microRNA (miRNA), or small interfering RNA (siRNA), (ii) the loading of siRNA/miRNA into an RNA Induced Silencing Complex (RISC), (iii) complementary base pairing between siRNA/miRNA with a targeted gene, and (iv) the cleavage or repression of a target gene with an Argonaute (AGO) protein. This natural RNAi pathway could introduce transgenes targeting various viral genes to induce gene silencing. Different RNAi pathways are reported for the artificial silencing of viral genes. These include Host-Induced Gene Silencing (HIGS), Virus-Induced Gene Silencing (VIGS), and Spray-Induced Gene Silencing (SIGS). There are significant limitations in HIGS and VIGS technology, such as lengthy and time-consuming processes, off-target effects, and public concerns regarding genetically modified (GM) transgenic plants. Here, we provide in-depth knowledge regarding SIGS, which efficiently provides RNAi resistance development against targeted genes without the need for GM transgenic plants. We give an overview of the defense system of plants against viral infection, including a detailed mechanism of RNAi, small RNA molecules and their types, and various kinds of RNAi pathways. This review will describe how RNA interference provides the antiviral defense, recent improvements, and their limitations.
Structural Insights into Iron Ions Accumulation in Dps Nanocage
Authors: Chesnokov Yury , Mozhaev Andrey , Kamyshinsky Roman , Gordienko Alexander , Dadinova Liubov
Published: May 2022

Dps (DNA-binding protein from starved cells) is well known for the structural protection of bacterial DNA by the formation of highly ordered intracellular assemblies under stress conditions. Moreover, this ferritin-like protein can perform fast oxidation of ferrous ions and subsequently accumulate clusters of ferric ions in its nanocages, thus providing the bacterium with physical and chemical protection. Here, cryo-electron microscopy was used to study the accumulation of iron ions in the nanocage of a Dps protein from Escherichia coli. We demonstrate that Fe2+ concentration in the solution and incubation time have an insignificant effect on the volume and the morphology of iron minerals formed in Dps nanocages. However, an increase in the Fe2+ level leads to an increase in the proportion of larger clusters and the clusters themselves are composed of discrete ~1–1.5 nm subunits.
Wnt/β-Catenin Signalling and Its Cofactor BCL9L Have an Oncogenic Effect in Bladder Cancer Cells
Authors: Kotolloshi Roland , Gajda Mieczyslaw , Grimm Marc-Oliver , Steinbach Daniel
Published: May 2022

Bladder cancer (BC) is characterised by a high recurrence and progression rate. However, the molecular mechanisms of BC progression remain poorly understood. BCL9L, a coactivator of β-catenin was mutated in the 5′ and 3′ untranslated regions (UTRs). We assessed the influence of UTRs mutations on BCL9L, and the role of BCL9L and Wnt/β-catenin signalling in BC cells. UTR mutations were analysed by a luciferase reporter. BCL9L protein was assessed by immunohistochemistry in BC tissues. Cell proliferation was examined by crystal violet staining and by the spheroid model. Moreover, migration and invasion were analysed in real-time using the xCelligence RTCA system. The A > T mutation at 3′ UTR of BCL9L reduces the luciferase reporter mRNA expression and activity. BCL9L is predominantly increased in dysplastic urothelial cells and muscle-invasive BC. Knockdown of BCL9L and inhibition of Wnt/β-catenin signalling significantly repress the proliferation, migration and invasion of Cal29 and T24. In addition, BCL9L knockdown reduces mRNA level of Wnt/β-catenin target genes in Cal29 but not in T24 cells. BCL9L and Wnt/β-catenin signalling play an oncogenic role in bladder cancer cells and seems to be associated with BC progression. Nevertheless, the involvement of BCL9L in Wnt/β-catenin signalling is cell-line specific.
Order vs. Disorder: Cholesterol and Omega-3 Phospholipids Determine Biomembrane Organization
Authors: de Santis Augusta , Scoppola Ernesto , Ottaviani Maria Francesca , Koutsioubas Alexandros , Barnsley Lester C. , Paduano Luigi , D’Errico Gerardino , Russo Krauss Irene
Published: May 2022

Lipid structural diversity strongly affects biomembrane chemico-physical and structural properties in addition to membrane-associated events. At high concentrations, cholesterol increases membrane order and rigidity, while polyunsaturated lipids are reported to increase disorder and flexibility. How these different tendencies balance in composite bilayers is still controversial. In this study, electron paramagnetic resonance spectroscopy, small angle neutron scattering, and neutron reflectivity were used to investigate the structural properties of cholesterol-containing lipid bilayers in the fluid state with increasing amounts of polyunsaturated omega-3 lipids. Either the hybrid 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine or the symmetric 1,2-docosahexaenoyl-sn-glycero-3-phosphocholine were added to the mixture of the naturally abundant 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine and cholesterol. Our results indicate that the hybrid and the symmetric omega-3 phospholipids affect the microscopic organization of lipid bilayers differently. Cholesterol does not segregate from polyunsaturated phospholipids and, through interactions with them, is able to suppress the formation of non-lamellar structures induced by the symmetric polyunsaturated lipid. However, this order/disorder balance leads to a bilayer whose structural organization cannot be ascribed to either a liquid ordered or to a canonical liquid disordered phase, in that it displays a very loose packing of the intermediate segments of lipid chains.
Age-Related DNA Methylation in Normal Kidney Tissue Identifies Epigenetic Cancer Risk Susceptibility Loci in the ANKRD34B and ZIC1 Genes
Authors: Serth Jürgen , Peters Inga , Hill Bastian , Hübscher Tatjana , Hennenlotter Jörg , Klintschar Michael , Kuczyk Markus Antonius
Published: May 2022

Both age-dependent and age-independent alteration of DNA methylation in human tissues are functionally associated with the development of many malignant and non-malignant human diseases. TCGA-KIRC data were biometrically analyzed to identify new loci with age-dependent DNA methylation that may contribute to tumor risk in normal kidney tissue. ANKRD34B and ZIC1 were evaluated as candidate genes by pyrosequencing of 539 tissues, including 239 normal autopsy, 157 histopathologically tumor-adjacent normal, and 143 paired tumor kidney samples. All candidate CpG loci demonstrated a strong correlation between relative methylation levels and age (R = 0.70–0.88, p < 2 × 10−16) and seven out of 10 loci were capable of predicting chronological age in normal kidney tissues, explaining 84% of the variance (R = 0.92). Moreover, significantly increased age-independent methylation was found for 9 out of 10 CpG loci in tumor-adjacent tissues, compared to normal autopsy tissues (p = 0.001–0.028). Comparing tumor and paired tumor-adjacent tissues revealed two patient clusters showing hypermethylation, one cluster without significant changes in methylation, and a smaller cluster demonstrating hypomethylation in the tumors (p < 1 × 10−10). Taken together, our results show the presence of additional methylation risk factors besides age for renal cancer in normal kidney tissue. Concurrent tumor-specific hypermethylation suggests a subset of these loci are candidates for epigenetic renal cancer susceptibility.
Temporal and Spatial Evolution of Green Invention Patent Applications in China
Authors: Wang Hongxia , Li Ming , Wang Zhiru , Zhang Xiaobo
Published: May 2022

This paper analyzes the temporal and spatial characteristics of green invention patent applications during 1985–2018. The results show that China’s green invention patent applications present five stages of slow development, slow growth, accelerating growth, rapid growth and booming. Green invention patent applications in the fields of energy conservation, alternative energy production and waste management have always been in the forefront, but there are relatively less green invention patent applications in transportation and nuclear power; which need to be further strengthened. Green invention patent applications show a high level of geographical agglomeration in space, mainly concentrated in the eastern region, followed by the central region, the western region and northeast region. During the study period, the differences among the four major regions, eastern, northeastern, central and western, showed a trend of first expanding and then narrowing, and the intra-regional differences were the main source of spatial differences. The number of green invention patent applications in the four regions also shifted in space during the research period. The temporal and spatial evolution characteristics are correlative to national and regional innovation policies. Aiming at solving the problems of unbalanced development in different categories of green invention patent applications and regions, this paper puts forward corresponding policy suggestions.
Finding Optimal Moving Target Defense Strategies: A Resilience Booster for Connected Cars
Authors: Ayrault Maxime , Kühne Ulrich , Borde Étienne
Published: May 2022

During their life-cycle, modern connected cars will have to face various and changing security threats. As for any critical embedded system, security fixes in the form of software updates need to be thoroughly verified and cannot be deployed on a daily basis. The system needs to commit to a defense strategy, while attackers can examine vulnerabilities and prepare possible exploits before attacking. In order to break this asymmetry, it can be advantageous to use proactive defenses, such as reconfiguring parts of the system configuration. However, resource constraints and losses in quality of service need to be taken into account for such Moving Target Defenses (MTDs). In this article, we present a game-theoretic model that can be used to compute an optimal MTD defense for a critical embedded system that is facing several attackers with different objectives. The game is resolved using off-the-shelf MILP solvers. We validated the method with an automotive use case and conducted extensive experiments to evaluate its scalability and stability.
A Proposed Translation of an Altai Mountain Inscription Presumed to Be from the 7th Century BC
Authors: Revesz Peter Z. , Varga Géza
Published: May 2022

The purpose of this study is to examine an Old Hungarian inscription that was recently found in the Altai mountain and was claimed to be over 2600 years old, which would make it the oldest extant example of the Old Hungarian script. A careful observation of the Altai script and a comparison with other Old Hungarian inscriptions was made, during which several errors were discovered in the interpretation of the Old Hungarian signs. After correcting for these errors that were apparently introduced by mixing up the inscription with underlying engravings of animal images, a new sequence of Old Hungarian signs was obtained and translated into a new text. The context of the text indicates that the inscription is considerably more recent and is unlikely to be earlier than the 19th century.
Insects in Art during an Age of Environmental Turmoil
Authors: Klein Barrett Anthony , Brosius Tierney
Published: May 2022

Humans are reshaping the planet in impressive, and impressively self-destructive, ways. Evidence and awareness of our environmental impact has failed to elicit meaningful change in reversing our behavior. A multifaceted approach to communicating human-induced environmental destruction is critical, and art can affect our behavior by its power to evoke emotions. Artists often use insects in their works because of our intimate and varied relationship with this diverse, abundant lineage of animals. We surveyed work by 73 artists featuring insects or insect bodily products to gauge how extensively artists are addressing anthropogenic environmental distress, and what insects they are choosing as subjects in the process. Categories often cited as contributing to species extinction are (1) habitat destruction, (2) invasive species, (3) pollution, (4) human population, and (5) overharvesting. After adding insect-specific categories of (6) decline of insect pollinators and (7) the intentional modification or extermination of insects, we categorized our surveyed works, confirming categorizations with 53 of the living artists. Forty-seven percent of the artists addressed habitat destruction or climate change, but some other categories were severely underrepresented, with almost no work explicitly addressing overpopulation or overharvesting. Artists favored Hymenoptera (62%) over potentially more species-rich orders. Recognizing these biases could alert scientists, artists, and others to more effectively communicate messages of universal importance.
Blood Pressure Increase following COVID-19 Vaccination: A Systematic Overview and Meta-Analysis
Authors: Angeli Fabio , Reboldi Gianpaolo , Trapasso Monica , Santilli Gabriella , Zappa Martina , Verdecchia Paolo
Published: May 2022

Coronavirus disease 2019 (COVID-19) vaccines proved a strong clinical efficacy against symptomatic or moderate/severe COVID-19 and are considered the most promising approach for curbing the pandemic. However, some questions regarding the safety of COVID-19 vaccines have been recently raised. Among adverse events to vaccines and despite a lack of signal during phase III clinical trials, an increase in blood pressure (BP) after COVID-19 vaccination has been reported as a potential adverse reaction. We systematically analyze this topic and undertook a meta-analysis of available data to estimate the proportion of patients with abnormal BP or raise in BP after vaccination. Six studies entered the final analysis. Overall, studies accrued 357,387 subjects with 13,444 events of abnormal or increased BP. After exclusion of outlier studies, the pooled estimated proportion of abnormal/increased BP after vaccination was 3.20% (95% CI: 1.62–6.21). Proportions of cases of stage III hypertension or hypertensive urgencies and emergencies was 0.6% (95% CI: 0.1% to 5.1%). In conclusion, abnormal BP is not rare after COVID-19 vaccination, but the basic mechanisms of this phenomenon are still unclear and require further research.
Effectiveness of Mild to Moderate Hypothermic Cardiopulmonary Bypass on Early Clinical Outcomes
Authors: Haider Adnan , Khwaja Irfan Azmatullah , Qureshi Abdul Basit , Khan Imran , Majeed Khalid Abdul , Yousaf Muhammad Shahbaz , Zaneb Hafsa , Rehman Abdul , Rabbani Imtiaz , Tahir Sajid Khan , Rehman Habib
Published: May 2022

Background: Intraoperative hypothermia is an integral part of cardiopulmonary bypass (CPB), and a precise degree of hypothermia may improve the early clinical outcomes of cardiac surgery. Presently, there is no agreement on an accurate, advantageous temperature range for routine use in CPB. To address this issue, we conducted a retrospective observational study to compare the effects of different hypothermic temperature ranges on primary (inotropic support, blood loss, and platelet count) and secondary (ventilation support and in-hospital stay) outcomes in patients undergoing elective cardiac surgery. Methods: Data were retrieved from the medical database of the Cardiovascular Surgery Department, King Edward Medical University, Lahore-Pakistan (a tertiary care hospital), dating from February 2015 to December 2017. Patients were divided into mild (34 °C to 36 °C), intermediate (31 °C to 33 °C), or moderate (28 °C to 30 °C) hypothermic groups. Results: Out of 275 patients, 245 (89.09%) fit the inclusion criteria. The cohort with mild hypothermic CPB temperatures presented better clinical outcomes in terms of requiring less inotropic support, less blood loss, fewer blood transfusions, improved platelet counts, shorter in-hospital stays, and required less ventilation support, when compared with other hypothermic groups. Conclusions: Mild hypothermic CPB (34 °C to 36 °C) may produce better clinical outcomes for cardiac surgery and improve the quality of health of cardiac patients.
Laparoscopic Fluorescence Guided Detection of Uterine Niche—The Next Step in Surgical Diagnosis and Treatment
Authors: Krentel Harald , Lauterbach Lisa-Kathrin , Mavrogiannis Georgios , De Wilde Rudy Leon
Published: May 2022

(1) Background: Uterine niche is a frequent condition in patients with a history of cesarean section. Although the relation to uterotomy seems to be clear, the exact pathogenesis is not fully understood. Uterine niche can easily be diagnosed by transvaginal ultrasound. It can be related to symptoms like dysmenorrhea, bleeding disorders, dysuria and dyspareunia. Uterine niche can be the cause of scar pregnancy, a rare form of ectopic pregnancy which can be related to severe complications; (2) Methods: We present a series of nine cases with different uterine niche related findings and discuss the diagnostic and therapeutic options reviewing the current literature and introduce a novel intrauterine ICG use for laparoscopic niche detection in one case; (3) Results: Most of uterine niche related symptoms and complications can be treated by a minimally invasive approach. Laparoscopic fluorescence guided niche detection is feasible; (4) Conclusions: Hysteroscopic and laparoscopic techniques allow the treatment of uterine niche related symptoms and complications. Intrauterine ICG application during fluorescence guided laparoscopy may allow easy niche detection.
Survival Impact of Residual Cancer Cells in Intraoperative Peritoneal Washes following Radical Hysterectomy for Cervical Cancer
Authors: Kim Jong Mi , Chong Gun Oh , Park Nora Jee-Young , Choi Yeong Eun , Lee Juhun , Lee Yoon Hee , Hong Dae Gy , Park Ji Young
Published: May 2022

Objective: Residual cancer cells (RCCs) contribute to cancer recurrence either because of tumor spillage or undetectable pre-existing micrometastatic tumor clones. We hypothesized that the pathologic evaluation of intraoperative peritoneal washes may reveal RCCs. The aim of this study was to evaluate the survival impact of RCCs identified in intraoperative peritoneal washes and their correlation with clinicopathologic parameters following radical hysterectomy for cervical cancer. Methods: A total of 229 patients with cervical cancer who underwent radical hysterectomy with pelvic and/or paraaortic lymphadenectomy were included. The intraoperative peritoneal washes after surgery were filtered through a strainer and the presence of tumor cells in the residual aspirate was determined. Univariate and multivariate analyses of clinicopathological parameters were performed to identify predictors of recurrence. Results: RCCs in intraoperative peritoneal washes were identified in 19 patients (8.3%). Multivariate analysis revealed that deep stromal invasion (hazard ratio [HR], 13.32; 95% confidence interval [CI], 1.81–98.27; p = 0.0111), lymph node metastasis (HR, 2.00; 95% CI, 1.01–3.99; p = 0.0482), and neoadjuvant chemotherapy (HR, 2.34; 95% CI, 1.89–4.61; p = 0.0139) were associated with tumor recurrence. However, the presence of RCCs was not associated with tumor recurrence (HR, 2.60; 95% CI, 0.74–9.11; p = 0.1352). Multiple logistic regression analysis revealed that RCCs were associated with neoadjuvant chemotherapy (odds ratio [OR], 0.22; 95% CI, 0.05–0.99; p = 0.0488) and large tumor size (OR, 4.16; 95% CI, 0.77–22.48; p = 0.0981). Conclusions: Although the presence of RCCs in intraoperative peritoneal washes do not significantly impact survival outcomes, there was a tendency of inferior survival outcomes in patients with RCCs. RCCs were associated with neoadjuvant chemotherapy and large tumor size.
Risk Factors for Non-Union after Open Reduction and Internal Fixation in Patients with Distal Humerus Fractures
Authors: Ku Ki-Hyeok , Baek Jong-Hun , Kim Myung-Seo
Published: May 2022

Background: Only a few studies have reported on the risk factors for non-union after open reduction and internal fixation (ORIF) in distal humerus fractures. Methods: We retrospectively reviewed 155 patients who underwent ORIF for distal humerus fractures from January 2008 to June 2020. Various patient factors, including body mass index (BMI), diabetes mellitus (DM), and combined fracture, as well as surgical factors, including fixation methods (e.g., orthogonal plate/parallel plate/single plate/tension bend wiring [TBW]) and combined fracture operations, were evaluated as risk factors for non-unions. Results: Among the patient factors, BMI (25.0 ± 3.4 vs. 22.7 ± 3.4, p = 0.032), DM (5/13 [38.5%] vs. 20/142 [14.1%], p = 0.038) and combined fracture (5/13 [38.5%] vs. 16/142 [11.3%], p = 0.018) were significantly different between groups with non-union and union. Among the surgical factors, combined fracture operation (5 [38.5%] vs. 9 [6.3%], p = 0.002) and the fixation method (3 [23.1%]/1 [7.7%]/4 [30.8%]/5 [38.5%] vs. 84 [59.2%]/7 [4.9%]/40 [28.2%]/11 [7.7%], p = 0.005) showed a significant difference between groups with non-union and union. Multivariate regression analysis showed that combined fracture operation (OR 10.467; 95% CI 1.880–58.257; p = 0.007) and TBW (OR 9.176; 95% CI 1.474–57.135; p = 0.018) among the fixation methods posed as a significant risk factor for non-union. Conclusions: The risk of non-union increased in patients who underwent surgery for another fracture combined with distal humerus fracture and in patients who underwent ORIF with TBW.
Effectiveness of Dupilumab in the Treatment of Patients with Severe Uncontrolled CRSwNP: A “Real-Life” Observational Study in the First Year of Treatment
Authors: De Corso Eugenio , Settimi Stefano , Montuori Claudio , Corbò Marco , Passali Giulio Cesare , Porru Davide Paolo , Lo Verde Simone , Spanu Camilla , Penazzi Daniele , Di Bella Giuseppe Alberto , Nucera Eleonora , Bonini Matteo , Paludetti Gaetano , Galli Jacopo
Published: May 2022

The aim of this study was to evaluate the efficacy of dupilumab in the treatment of severe uncontrolled Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), with or without asthma as add-on therapy with intra-nasal corticosteroids in a real-life setting over the first year of treatment. Our data demonstrated that subcutaneous 300 mg dupilumab administered at home via a pre-filled auto-injector every two weeks, based on indications set by the Italian Medicines Agency, was rapidly effective in reducing the size of polyps, decreasing symptoms of disease, improving quality of life, and recovering olfaction. Significant improvement was observed after only 15 days of treatment, and it progressively increased at 6 and 12 months. Dupilumab was also effective in reducing the local nasal eosinophilic infiltrate, in decreasing the need for surgery and/or oral corticosteroids, and in improving control of associated comorbidities such as chronic eosinophilic otitis media and bronchial asthma. After 12 months of treatment, 96.5% of patients had a moderate/excellent response. From our data, it was evident that there was a group of patients that showed a very early response within one month of therapy, another group with early response within six months from baseline, and a last group that improved later within 12 months. The results of this study support the use of dupilumab as an effective option in the current standard of care for patients affected by severe uncontrolled CRSwNP.