bluuebunny/crossref_metadata_2025 huggingface dataset:
An Integrated Transcriptomic Approach to Identify Molecular Markers of Calcineurin Inhibitor Nephrotoxicity in Pediatric Kidney Transplant Recipients
Authors: Rhone Erika T. , Bardhi Elissa , Bontha Sai Vineela , Walker Patrick D. , Almenara Jorge A. , Dumur Catherine I. , Cathro Helen , Maluf Daniel , Mas Valeria
Published: May 2021

Calcineurin inhibitors are highly efficacious immunosuppressive agents used in pediatric kidney transplantation. However, calcineurin inhibitor nephrotoxicity (CNIT) has been associated with the development of chronic renal allograft dysfunction and decreased graft survival. This study evaluated 37 formalin-fixed paraffin-embedded biopsies from pediatric kidney transplant recipients using gene expression profiling. Normal allograft samples (n = 12) served as negative controls and were compared to biopsies exhibiting CNIT (n = 11). The remaining samples served as positive controls to validate CNIT marker specificity and were characterized by other common causes of graft failure such as acute rejection (n = 7) and interstitial fibrosis/tubular atrophy (n = 7). MiRNA profiles served as the platform for data integration. Oxidative phosphorylation and mitochondrial dysfunction were the top molecular pathways associated with overexpressed genes in CNIT samples. Decreased ATP synthesis was identified as a significant biological function in CNIT, while key toxicology pathways included NRF2-mediated oxidative stress response and increased permeability transition of mitochondria. An integrative analysis demonstrated a panel of 13 significant miRNAs and their 33 CNIT-specific gene targets involved with mitochondrial activity and function. We also identified a candidate panel of miRNAs/genes, which may serve as future molecular markers for CNIT diagnosis as well as potential therapeutic targets.
Carbonized Lysine-Nanogels Protect against Infectious Bronchitis Virus
Authors: Chou Ding-Li , Mao Ju-Yi , Anand Anisha , Lin Han-Jia , Lin John Han-You , Tseng Ching-Ping , Huang Chih-Ching , Wang Hsian-Yu
Published: May 2021

In this study, we demonstrate the synthesis of carbonized nanogels (CNGs) from an amino acid (lysine hydrochloride) using a simple pyrolysis method, resulting in effective viral inhibition properties against infectious bronchitis virus (IBV). The viral inhibition of CNGs was studied using both in vitro (bovine ephemeral fever virus (BEFV) and pseudorabies virus (PRV)) and in ovo (IBV) models, which indicated that the CNGs were able to prevent virus attachment on the cell membrane and penetration into the cell. A very low concentration of 30 μg mL−1 was found to be effective (>98% inhibition) in IBV-infected chicken embryos. The hatching rate and pathology of IBV-infected chicken embryos were greatly improved in the presence of CNGs. CNGs with distinctive virus-neutralizing activities show great potential as a virostatic agent to prevent the spread of avian viruses and to alleviate the pathology of infected avian species.
Analysis and Interpretation of the Impact of Missense Variants in Cancer
Authors: Petrosino Maria , Novak Leonore , Pasquo Alessandra , Chiaraluce Roberta , Turina Paola , Capriotti Emidio , Consalvi Valerio
Published: May 2021

Large scale genome sequencing allowed the identification of a massive number of genetic variations, whose impact on human health is still unknown. In this review we analyze, by an in silico-based strategy, the impact of missense variants on cancer-related genes, whose effect on protein stability and function was experimentally determined. We collected a set of 164 variants from 11 proteins to analyze the impact of missense mutations at structural and functional levels, and to assess the performance of state-of-the-art methods (FoldX and Meta-SNP) for predicting protein stability change and pathogenicity. The result of our analysis shows that a combination of experimental data on protein stability and in silico pathogenicity predictions allowed the identification of a subset of variants with a high probability of having a deleterious phenotypic effect, as confirmed by the significant enrichment of the subset in variants annotated in the COSMIC database as putative cancer-driving variants. Our analysis suggests that the integration of experimental and computational approaches may contribute to evaluate the risk for complex disorders and develop more effective treatment strategies.
Neuroprotective Effects of Thiamine and Precursors with Higher Bioavailability: Focus on Benfotiamine and Dibenzoylthiamine
Authors: Sambon Margaux , Wins Pierre , Bettendorff Lucien
Published: May 2021

Thiamine (vitamin B1) is essential for brain function because of the coenzyme role of thiamine diphosphate (ThDP) in glucose and energy metabolism. In order to compensate thiamine deficiency, several thiamine precursors with higher bioavailability were developed since the 1950s. Among these, the thioester benfotiamine (BFT) has been extensively studied and has beneficial effects both in rodent models of neurodegeneration and in human clinical studies. BFT has antioxidant and anti-inflammatory properties that seem to be mediated by a mechanism independent of the coenzyme function of ThDP. BFT has no adverse effects and improves cognitive outcome in patients with mild Alzheimer’s disease (AD). Recent in vitro studies show that another thiamine thioester, dibenzoylthiamine (DBT) is even more efficient that BFT, especially with respect to its anti-inflammatory potency. Thiamine thioesters have pleiotropic properties linked to an increase in circulating thiamine concentrations and possibly in hitherto unidentified metabolites in particular open thiazole ring derivatives. The identification of the active neuroprotective derivatives and the clarification of their mechanism of action open extremely promising perspectives in the field of neurodegenerative, neurodevelopmental and psychiatric conditions.
Inflammation-Induced Tumorigenesis and Metastasis
Authors: Hibino Sana , Kawazoe Tetsuro , Kasahara Hidenori , Itoh Shinji , Ishimoto Takatsugu , Sakata-Yanagimoto Mamiko , Taniguchi Koji
Published: May 2021

Inflammation, especially chronic inflammation, plays a pivotal role in tumorigenesis and metastasis through various mechanisms and is now recognized as a hallmark of cancer and an attractive therapeutic target in cancer. In this review, we discuss recent advances in molecular mechanisms of how inflammation promotes tumorigenesis and metastasis and suppresses anti-tumor immunity in various types of solid tumors, including esophageal, gastric, colorectal, liver, and pancreatic cancer as well as hematopoietic malignancies.
Genomic Approaches to Identify Molecular Bases of Crop Resistance to Diseases and to Develop Future Breeding Strategies
Authors: Mores Antonia , Borrelli Grazia Maria , Laidò Giovanni , Petruzzino Giuseppe , Pecchioni Nicola , Amoroso Luca Giuseppe Maria , Desiderio Francesca , Mazzucotelli Elisabetta , Mastrangelo Anna Maria , Marone Daniela
Published: May 2021

Plant diseases are responsible for substantial crop losses each year and affect food security and agricultural sustainability. The improvement of crop resistance to pathogens through breeding represents an environmentally sound method for managing disease and minimizing these losses. The challenge is to breed varieties with a stable and broad-spectrum resistance. Different approaches, from markers to recent genomic and ‘post-genomic era’ technologies, will be reviewed in order to contribute to a better understanding of the complexity of host–pathogen interactions and genes, including those with small phenotypic effects and mechanisms that underlie resistance. An efficient combination of these approaches is herein proposed as the basis to develop a successful breeding strategy to obtain resistant crop varieties that yield higher in increasing disease scenarios.
Epigenetic Distribution of Recombinant Plant Chromosome Fragments in a Human–Arabidopsis Hybrid Cell Line
Authors: Liaw YengMun , Liu Yikun , Teo CheeHow , Cápal Petr , Wada Naoki , Fukui Kiichi , Doležel Jaroslav , Ohmido Nobuko
Published: May 2021

Methylation systems have been conserved during the divergence of plants and animals, although they are regulated by different pathways and enzymes. However, studies on the interactions of the epigenomes among evolutionarily distant organisms are lacking. To address this, we studied the epigenetic modification and gene expression of plant chromosome fragments (~30 Mb) in a human–Arabidopsis hybrid cell line. The whole-genome bisulfite sequencing results demonstrated that recombinant Arabidopsis DNA could retain its plant CG methylation levels even without functional plant methyltransferases, indicating that plant DNA methylation states can be maintained even in a different genomic background. The differential methylation analysis showed that the Arabidopsis DNA was undermethylated in the centromeric region and repetitive elements. Several Arabidopsis genes were still expressed, whereas the expression patterns were not related to the gene function. We concluded that the plant DNA did not maintain the original plant epigenomic landscapes and was under the control of the human genome. This study showed how two diverging genomes can coexist and provided insights into epigenetic modifications and their impact on the regulation of gene expressions between plant and animal genomes.
Deficient Leptin Cellular Signaling Plays a Key Role in Brain Ultrastructural Remodeling in Obesity and Type 2 Diabetes Mellitus
Authors: Hayden Melvin R. , Banks William A.
Published: May 2021

The triad of obesity, metabolic syndrome (MetS), Type 2 diabetes mellitus (T2DM) and advancing age are currently global societal problems that are expected to grow over the coming decades. This triad is associated with multiple end-organ complications of diabetic vasculopathy (maco-microvessel disease), neuropathy, retinopathy, nephropathy, cardiomyopathy, cognopathy encephalopathy and/or late-onset Alzheimer’s disease. Further, obesity, MetS, T2DM and their complications are associated with economical and individual family burdens. This review with original data focuses on the white adipose tissue-derived adipokine/hormone leptin and how its deficient signaling is associated with brain remodeling in hyperphagic, obese, or hyperglycemic female mice. Specifically, the ultrastructural remodeling of the capillary neurovascular unit, brain endothelial cells (BECs) and their endothelial glycocalyx (ecGCx), the blood-brain barrier (BBB), the ventricular ependymal cells, choroid plexus, blood-cerebrospinal fluid barrier (BCSFB), and tanycytes are examined in female mice with impaired leptin signaling from either dysfunction of the leptin receptor (DIO and db/db models) or the novel leptin deficiency (BTBR ob/ob model).
Simulated Microgravity Remodels Extracellular Matrix of Osteocommitted Mesenchymal Stromal Cells
Authors: Zhivodernikov Ivan , Ratushnyy Andrey , Buravkova Ludmila
Published: May 2021

The extracellular matrix (ECM) is the principal structure of bone tissue. Long-term spaceflights lead to osteopenia, which may be a result of the changes in composition as well as remodeling of the ECM by osteogenic cells. To elucidate the cellular effects of microgravity, human mesenchymal stromal cells (MSCs) and their osteocommitted progeny were exposed to simulated microgravity (SMG) for 10 days using random positioning machine (RPM). After RPM exposure, an imbalance of MSC collagen/non-collagen ratio at the expense of a decreased level of collagenous proteins was detected. At the same time, the secretion of proteases (cathepsin A, cathepsin D, MMP3) was increased. No significant effects of SMG on the expression of stromal markers and cell adhesion molecules on the MSC surface were noted. Upregulation of COL11A1, CTNND1, TIMP3, and TNC and downregulation of HAS1, ITGA3, ITGB1, LAMA3, MMP1, and MMP11 were detected in RPM exposed MSCs. ECM-associated transcriptomic changes were more pronounced in osteocommitted progeny. Thus, 10 days of SMG provokes a decrease in the collagenous components of ECM, probably due to the decrease in collagen synthesis and activation of proteases. The presented data demonstrate that ECM-associated molecules of both native and osteocommitted MSCs may be involved in bone matrix reorganization during spaceflight.
Contribution of Massive Mitochondrial Fusion and Subsequent Fission in the Plant Life Cycle to the Integrity of the Mitochondrion and Its Genome
Authors: Rose Ray J.
Published: May 2021

Plant mitochondria have large genomes to house a small number of key genes. Most mitochondria do not contain a whole genome. Despite these latter characteristics, the mitochondrial genome is faithfully maternally inherited. To maintain the mitochondrial genes—so important for energy production—the fusion and fission of mitochondria are critical. Fission in plants is better understood than fusion, with the dynamin-related proteins (DRP 3A and 3B) driving the constriction of the mitochondrion. How the endoplasmic reticulum and the cytoskeleton are linked to the fission process is not yet fully understood. The fusion mechanism is less well understood, as obvious orthologues are not present. However, there is a recently described gene, MIRO2, that appears to have a significant role, as does the ER and cytoskeleton. Massive mitochondrial fusion (MMF or hyperfusion) plays a significant role in plants. MMF occurs at critical times of the life cycle, prior to flowering, in the enlarging zygote and at germination, mixing the cells’ mitochondrial population—the so-called “discontinuous whole”. MMF in particular aids genome repair, the conservation of critical genes and possibly gives an energy boost to important stages of the life cycle. MMF is also important in plant regeneration, an important component of plant biotechnology.
METTL8 mRNA Methyltransferase Enhances Cancer Cell Migration via Direct Binding to ARID1A
Authors: Lee Shin-Ae , Lee Kang-Hoon , Kim Huisu , Cho Je-Yoel
Published: May 2021

The association of RNA modification in cancer has recently been highlighted. Methyltransferase like 8 (METTL8) is an enzyme and its role in mRNA m3C modification has barely been studied. In this study, we found that METTL8 expression was significantly up-regulated in canine mammary tumor and investigated its functional roles in the tumor process, including cancer cell proliferation and migration. METTL8 expression was up-regulated in most human breast cancer cell lines tested and decreased by Yin Yang 1 (YY1) transcription factor knockdown, suggesting that YY1 is a regulating transcription factor. The knockdown of METTL8 attenuated tumor cell growth and strongly blocked tumor cell migration. AT-rich interactive domain-containing protein 1A (ARID1A) was identified as a candidate mRNA by METTL8. ARID1A mRNA binds to METTL8 protein. ARID1A mRNA expression was not changed by METTL8 knockdown, but ARID1A protein level was significantly increased. Collectively, our study indicates that METTL8 up-regulated by YY1 in breast cancer plays an important role in cancer cell migration through the mRNA modification of ARID1A, resulting in the attenuation of its translation.
Design and Pharmacodynamics of Recombinant Fungus Defensin NZL with Improved Activity against Staphylococcus hyicus In Vitro and In Vivo
Authors: Liu He , Yang Na , Teng Da , Mao Ruoyu , Hao Ya , Ma Xuanxuan , Wang Jianhua
Published: May 2021

Staphylococcus hyicus is recognized as a leading pathogen of exudative epidermitis in modern swine industry. Antimicrobial peptides are attractive candidates for development as potential therapeutics to combat the serious threats of the resistance of S. hyicus. In this study, a series of derivatives were designed based on the NZ2114 template with the aim of obtaining peptides with more potent antimicrobial activity through changing net positive charge or hydrophobicity. Among them, a variant designated as NZL was highly expressed in Pichia pastoris (P. pastoris) with total secreted protein of 1505 mg/L in a 5-L fermenter and exhibited enhanced antimicrobial activity relative to parent peptide NZ2114. Additionally, NZL could kill over 99% of S. hyicus NCTC10350 in vitro within 8 h and in Hacat cells. The results of membrane permeabilization assay, morphological observations, peptide localization assay showed that NZL had potent activity against S. hyicus, which maybe kill S. hyicus through action on the cell wall. NZL also showed an effective therapy in a mouse peritonitis model caused by S. hyicus, superior to NZ2114 or ceftriaxone. Overall, these findings can contribute to explore a novel potential candidate against S. hyicus infections.
Structural Perspectives on the Mechanism of Soluble Guanylate Cyclase Activation
Authors: Wittenborn Elizabeth C. , Marletta Michael A.
Published: May 2021

The enzyme soluble guanylate cyclase (sGC) is the prototypical nitric oxide (NO) receptor in humans and other higher eukaryotes and is responsible for transducing the initial NO signal to the secondary messenger cyclic guanosine monophosphate (cGMP). Generation of cGMP in turn leads to diverse physiological effects in the cardiopulmonary, vascular, and neurological systems. Given these important downstream effects, sGC has been biochemically characterized in great detail in the four decades since its discovery. Structures of full-length sGC, however, have proven elusive until very recently. In 2019, advances in single particle cryo–electron microscopy (cryo-EM) enabled visualization of full-length sGC for the first time. This review will summarize insights revealed by the structures of sGC in the unactivated and activated states and discuss their implications in the mechanism of sGC activation.
Selective Inhibition of PDE4B Reduces Binge Drinking in Two C57BL/6 Substrains
Authors: Jimenez Chavez C. Leonardo , Bryant Camron D. , Munn-Chernoff Melissa A. , Szumlinski Karen K.
Published: May 2021

Cyclic AMP (cAMP)-dependent signaling is highly implicated in the pathophysiology of alcohol use disorder (AUD), with evidence supporting the efficacy of inhibiting the cAMP hydrolyzing enzyme phosphodiesterase 4 (PDE4) as a therapeutic strategy for drinking reduction. Off-target emetic effects associated with non-selective PDE4 inhibitors has prompted the development of selective PDE4 isozyme inhibitors for treating neuropsychiatric conditions. Herein, we examined the effect of a selective PDE4B inhibitor A33 (0–1.0 mg/kg) on alcohol drinking in both female and male mice from two genetically distinct C57BL/6 substrains. Under two different binge-drinking procedures, A33 pretreatment reduced alcohol intake in male and female mice of both substrains. In both drinking studies, there was no evidence for carry-over effects the next day; however, we did observe some sign of tolerance to A33’s effect on alcohol intake upon repeated, intermittent, treatment (5 injections of 1.0 mg/kg, every other day). Pretreatment with 1.0 mg/kg of A33 augmented sucrose intake by C57BL/6NJ, but not C57BL/6J, mice. In mice with a prior history of A33 pretreatment during alcohol-drinking, A33 (1.0 mg/kg) did not alter spontaneous locomotor activity or basal motor coordination, nor did it alter alcohol’s effects on motor activity, coordination or sedation. In a distinct cohort of alcohol-naïve mice, acute pretreatment with 1.0 mg/kg of A33 did not alter motor performance on a rotarod and reduced sensitivity to the acute intoxicating effects of alcohol. These data provide the first evidence that selective PDE4B inhibition is an effective strategy for reducing excessive alcohol intake in murine models of binge drinking, with minimal off-target effects. Despite reducing sensitivity to acute alcohol intoxication, PDE4B inhibition reduces binge alcohol drinking, without influencing behavioral sensitivity to alcohol in alcohol-experienced mice. Furthermore, A33 is equally effective in males and females and exerts a quantitatively similar reduction in alcohol intake in mice with a genetic predisposition for high versus moderate alcohol preference. Such findings further support the safety and potential clinical utility of targeting PDE4 for treating AUD.
MMP-9 Deletion Attenuates Arteriovenous Fistula Neointima through Reduced Perioperative Vascular Inflammation
Authors: Shih Yu-Chung , Chen Po-Yuan , Ko Tai-Ming , Huang Po-Hsun , Ma Hsu , Tarng Der-Cherng
Published: May 2021

Matrix metalloproteinase 9 (MMP-9) expression is upregulated in vascular inflammation and participates in vascular remodeling, including aneurysm dilatation and arterial neointima development. Neointima at the arteriovenous (AV) fistula anastomosis site primarily causes AV fistula stenosis and failure; however, the effects of MMP-9 on perioperative AV fistula remodeling remain unknown. Therefore, we created AV fistulas (end-to-side anastomosis) in wild-type (WT) and MMP-9 knockout mice with chronic kidney disease to further clarify this. Neointima progressively developed in the AV fistula venous segment of WT mice during the four-week postoperative course, and MMP-9 knockout increased the lumen area and attenuated neointima size by reducing smooth muscle cell and collagen components. Early perioperative AV fistula mRNA sequencing data revealed that inflammation-related gene sets were negatively enriched in AV fistula of MMP-9 knockout mice compared to that in WT mice. qPCR results also showed that inflammatory genes, including tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), were downregulated. In addition, Western blot results showed that MMP-9 knockout reduced CD44 and RAC-alpha serine/threonine-protein kinase (Akt) and extracellular signal-regulated kinases (ERK) phosphorylation. In vitro, MMP-9 addition enhanced IL-6 and MCP-1 expression in vascular smooth muscle cells, as well as cell migration, which was reversed by an MMP-9 inhibitor. In conclusion, MMP-9 knockout attenuated AV fistula stenosis by reducing perioperative vascular inflammation.
Proteolytic α-Synuclein Cleavage in Health and Disease
Authors: Bluhm Alexandra , Schrempel Sarah , von Hörsten Stephan von , Schulze Anja , Roßner Steffen
Published: May 2021

In Parkinson’s disease, aggregates of α-synuclein within Lewy bodies and Lewy neurites represent neuropathological hallmarks. However, the cellular and molecular mechanisms triggering oligomeric and fibrillary α-synuclein aggregation are not fully understood. Recent evidence indicates that oxidative stress induced by metal ions and post-translational modifications such as phosphorylation, ubiquitination, nitration, glycation, and SUMOylation affect α-synuclein conformation along with its aggregation propensity and neurotoxic profiles. In addition, proteolytic cleavage of α-synuclein by specific proteases results in the formation of a broad spectrum of fragments with consecutively altered and not fully understood physiological and/or pathological properties. In the present review, we summarize the current knowledge on proteolytical α-synuclein cleavage by neurosin, calpain-1, cathepsin D, and matrix metalloproteinase-3 in health and disease. We also shed light on the contribution of the same enzymes to proteolytical processing of pathogenic proteins in Alzheimer’s disease and report potential cross-disease mechanisms of pathogenic protein aggregation.
Hereditary Hyperferritinemia Cataract Syndrome: Ferritin L Gene and Physiopathology behind the Disease—Report of New Cases
Authors: Celma Nos Ferran , Hernández Gonzalo , Ferrer-Cortès Xènia , Hernandez-Rodriguez Ines , Navarro-Almenzar Begoña , Fuster José Luis , Bermúdez Cortés Mar , Pérez-Montero Santiago , Tornador Cristian , Sanchez Mayka
Published: May 2021

Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare disease characterized by high serum ferritin levels, congenital bilateral cataracts, and the absence of tissue iron overload. This disorder is produced by mutations in the iron responsive element (IRE) located in the 5′ untranslated regions (UTR) of the light ferritin (FTL) gene. A canonical IRE is a mRNA structure that interacts with the iron regulatory proteins (IRP1 and IRP2) to post-transcriptionally regulate the expression of proteins related to iron metabolism. Ferritin L and H are the proteins responsible for iron storage and intracellular distribution. Mutations in the FTL IRE abrogate the interaction of FTL mRNA with the IRPs, and de-repress the expression of FTL protein. Subsequently, there is an overproduction of ferritin that accumulates in serum (hyperferritinemia) and excess ferritin precipitates in the lens, producing cataracts. To illustrate this disease, we report two new families affected with hereditary hyperferritinemia-cataract syndrome with previous known mutations. In the diagnosis of congenital bilateral cataracts, HHCS should be taken into consideration and, therefore, it is important to test serum ferritin levels in patients with cataracts.
Processed Animal Proteins from Insect and Poultry By-Products in a Fish Meal-Free Diet for Rainbow Trout: Impact on Intestinal Microbiota and Inflammatory Markers
Authors: Gaudioso Giulia , Marzorati Giulia , Faccenda Filippo , Weil Tobias , Lunelli Fernando , Cardinaletti Gloriana , Marino Giovanna , Olivotto Ike , Parisi Giuliana , Tibaldi Emilio , Tuohy Kieran Michael , Fava Francesca
Published: May 2021

Sustainability of aquaculture is tied to the origin of feed ingredients. In search of sustainable fish meal-free formulations for rainbow trout, we evaluated the effect of Hermetia illucens meal (H) and poultry by-product meal (P), singly (10, 30, and 60% of either H or P) or in combination (10% H + 50% P, H10P50), as partial replacement of vegetable protein (VM) on gut microbiota (GM), inflammatory, and immune biomarkers. Fish fed the mixture H10P50 had the best growth performance. H, P, and especially the combination H10P50 partially restored α-diversity that was negatively affected by VM. Diets did not differ in the Firmicutes:Proteobacteria ratio, although the relative abundance of Gammaproteobacteria was reduced in H and was higher in P and in the fishmeal control. H had higher relative abundance of chitin-degrading Actinomyces and Bacillus, Dorea, and Enterococcus. Actinomyces was also higher in H feed, suggesting feed-chain microbiome transmission. P increased the relative abundance of protein degraders Paeniclostridium and Bacteroidales. IL-1β, IL-10, TGF-β, COX-2, and TCR-β gene expression in the midgut and head kidney and plasma lipopolysaccharide (LPS) revealed that the diets did not compromise the gut barrier function or induce inflammation. H, P, and H10P50 therefore appear valid protein sources in fishmeal-free aquafeeds.
The Emerging Role of microRNA in Periodontitis: Pathophysiology, Clinical Potential and Future Molecular Perspectives
Authors: Santonocito Simona , Polizzi Alessandro , Palazzo Giuseppe , Isola Gaetano
Published: May 2021

During the last few decades, it has been established that messenger ribonucleic acid (mRNA) transcription does not inevitably lead to protein translation, but there are numerous processes involved in post-transcriptional regulation, which is a continuously developing field of research. MicroRNAs (miRNAs) are a group of small non-coding RNAs, which negatively regulate protein expression and are implicated in several physiological and pathological mechanisms. Aberrant expression of miRNAs triggers dysregulation of multiple cellular processes involved in innate and adaptive immune responses. For many years, it was thought that miRNAs acted only within the cell in which they were synthesised, but, recently, they have been found outside cells bound to lipids and proteins, or enclosed in extracellular vesicles, namely exosomes. They can circulate throughout the body, transferring information between cells and altering gene expression in the recipient cells, as they can fuse with and be internalised by the recipient cells. Numerous studies on miRNAs have been conducted in order to identify possible biomarkers that can be used in the diagnosis of periodontal disease. However, as therapeutic agents, single miRNAs can target several genes and influence multiple regulatory networks. The aim of this review was to examine the molecular role of miRNAs and exosomes in the pathophysiology of periodontal disease and to evaluate possible clinical and future implications for a personalised therapeutical approach.
Loss of PKGIβ/IRAG1 Signaling Causes Anemia-Associated Splenomegaly
Authors: Majer Michael , Prueschenk Sally , Schlossmann Jens
Published: May 2021

Inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate 1 (IRAG1) is a substrate protein of the NO/cGMP-signaling pathway and forms a ternary complex with the cGMP-dependent protein kinase Iβ (PKGIβ) and the inositol triphosphate receptor I (IP3R-I). Functional studies about IRAG1 exhibited that IRAG1 is specifically phosphorylated by the PKGIβ, regulating cGMP-mediated IP3-dependent Ca2+-release. IRAG1 is widely distributed in murine tissues, e.g., in large amounts in smooth muscle-containing tissues and platelets, but also in lower amounts, e.g., in the spleen. The NO/cGMP/PKGI signaling pathway is important in several organ systems. A loss of PKGI causes gastrointestinal disorders, anemia and splenomegaly. Due to the similar tissue distribution of the PKGIβ to IRAG1, we investigated the pathophysiological functions of IRAG1 in this context. Global IRAG1-KO mice developed gastrointestinal bleeding, anemia-associated splenomegaly and iron deficiency. Additionally, Irag1-deficiency altered the protein levels of some cGMP/PKGI signaling proteins—particularly a strong decrease in the PKGIβ—in the colon, spleen and stomach but did not change mRNA-expression of the corresponding genes. The present work showed that a loss of IRAG1 and the PKGIβ/IRAG1 signaling has a crucial function in the development of gastrointestinal disorders and anemia-associated splenomegaly. Furthermore, global Irag1-deficient mice are possible in vivo model to investigate PKGIβ protein functions.
Design and Implementation of Intelligent Gateway System for Monitoring Livestock and Poultry Feeding Environment Based on Bluetooth Low Energy
Authors: Du Yawen , Sun Guiling , Zheng Bowen , Qu Yunlong
Published: May 2021

This article proposes a gateway system design method applied to the monitoring of a breeding environment based on Bluetooth low energy consumption. Through the queue mechanism and buffer management method, the key information that has the greatest impact on the monitoring effect is sent first, and the feedback mechanism is used to adjust the sampling period of the node in conjunction with the abnormal degree of the monitoring parameter. Experimental results show that the system constructed in this article significantly shortens the transmission delay of key information, with an average packet loss rate of 1.09%. Compared with the traditional method, this method is more timely and effective in handling abnormal data. It effectively solves the short distance and low efficiency of Bluetooth “point-to-multipoint” communication in the case of high data concurrency, and improves the reliability and stability of communication. In turn, the losses caused by environmental mutations are reduced.
Erectile Dysfunction Is a Hallmark of Cardiovascular Disease: Unavoidable Matter of Fact or Opportunity to Improve Men’s Health?
Authors: Yannas Dimitri , Frizza Francesca , Vignozzi Linda , Corona Giovanni , Maggi Mario , Rastrelli Giulia
Published: May 2021

Erectile dysfunction (ED) is an early manifestation of cardiovascular (CV) disease. For this reason, men with ED should be carefully assessed for CV risk factors in order to prevent future major adverse CV events (MACE). Traditional risk factors are not found in all subjects at high CV risk. In fact, a relevant proportion of MACE occurs in men who are apparently risk factor free. In men with ED, it is important to take into account not only traditional risk factors but also unconventional ones. Several parameters that derive from good clinical assessment of subjects with ED have proven to be valuable predictors of MACE. These include family history of cardiometabolic events, alcohol abuse, fatherhood, decreased partner’s sexual interest, severe impairment in erection during intercourse or during masturbation, impaired fasting glucose, increased triglycerides, obesity even without metabolic complications, decreased penile blood flows or impaired response to an intra-cavernosal injection test. Recognizing these risk factors may help in identifying, among subjects with ED, those who merit stricter lifestyle or pharmacological interventions to minimize their CV risk. Effective correction of risk factors in ED men considered as high risk, besides reducing CV risk, is also able to improve erectile function.
Novelties in Imaging of Thoracic Sarcoidosis
Authors: Calandriello Lucio , D’Abronzo Rosa , Pasciuto Giuliana , Cicchetti Giuseppe , del Ciello Annemilia , Farchione Alessandra , Strappa Cecilia , Manfredi Riccardo , Larici Anna Rita
Published: May 2021

Sarcoidosis is a systemic granulomatous disease affecting various organs, and the lungs are the most commonly involved. According to guidelines, diagnosis relies on a consistent clinical picture, histological demonstration of non-caseating granulomas, and exclusion of other diseases with similar histological or clinical picture. Nevertheless, chest imaging plays an important role in both diagnostic assessment, allowing to avoid biopsy in some situations, and prognostic evaluation. Despite the demonstrated lower sensitivity of chest X-ray (CXR) in the evaluation of chest findings compared to high-resolution computed tomography (HRCT), CXR still retains a pivotal role in both diagnostic and prognostic assessment in sarcoidosis. Moreover, despite the huge progress made in the field of radiation dose reduction, chest magnetic resonance (MR), and quantitative imaging, very little research has focused on their application in sarcoidosis. In this review, we aim to describe the latest novelties in diagnostic and prognostic assessment of thoracic sarcoidosis and to identify the fields of research that require investigation.
Identification of the Representative Primary Biliary Cholangitis Cohort in Taiwan: A Comparison of Four Nationwide Cohorts
Authors: Chen Cheng-Jen , Cheng Jur-Shan , Wang Haw-En , Huang Chun-Wen , Hu Jing-Hong , Chen Wei-Ting , Chang Ming-Yu , Ku Hsin-Ping , Lin Cheng-Yu , Chien Rong-Nan , Chang Ming-Ling
Published: May 2021

Background/Purpose: The rates and outcomes of primary biliary cholangitis (PBC) in Taiwan remain unclear. Methods: A nationwide population-based cohort study (Taiwan National Health Insurance Research Database, 2002–2015) was conducted. Data from four PBC cohorts with various definitions were compared (cohort 1 (C1): ICD-9-CM (571.6); C2: alkaline phosphatase (Alk-P) and antimitochondrial antibody (AMA) measurements; C3: Alk-p and AMA measurements and ursodeoxycholic acid (UDCA) treatment; C4: ICD-9-CM (571.6), Alk-p and AMA measurements and UDCA treatment). Results: The average prevalence rate ranged from 9.419/105 (C4) to 307.658/105 (C2), and the female-to-male ratio ranged from 1.192 (C1) to 3.66 (C4). Prevalence rates increased over time in all cohorts. The average incidence rates ranged from 1.456/105 (C4) to 66.386/105 (C2). Incidence rates decreased over time in C1 (−9.09%, p < 0.0001) and C4 (−6.68%, p < 0.0001) and remained steady in the others. C4 had the lowest prevalence and incidence rates and highest female-to-male ratio. Cirrhosis rates ranged from 7.21% (C2) to 39.34% (C4), hepatoma rates ranged from 2.77%(C2) to 6.66%(C1), liver transplantation (LT) rates ranged from 1.07% (C2) to 6.77% (C4), and mortality rates ranged from 18.24% (C2) to 47.36% (C1). C4 had the highest LT (6.77%), osteoporosis (13.87%) and dyslipidemia rates (17.21%). Conclusions: Based on the reported ranges of reasonable rates, female predominance and characteristic outcomes, C4 was the most representative Taiwanese PBC cohort, with average prevalence and incidence rates of 9.419/105 and 1.456/105, respectively, and a female-to-male ratio of 3.66. In a 14-year period, cirrhosis, hepatoma, LT, and mortality were noted in 39.34%, 5.52%, 6.77%, and 34.22% of C4 patients, respectively.
The Relation of Clinic and Ambulatory BP with the Risk of Cardiovascular Events and All-Cause Mortality among Patients on Peritoneal Dialysis
Authors: Georgianos Panagiotis I. , Vaios Vasilios , Zebekakis Pantelis E. , Liakopoulos Vassilios
Published: May 2021

Large observational studies showed a U-shaped association of clinic blood pressure (BP) with mortality among patients undergoing peritoneal dialysis (PD). Whether ambulatory BP provides a more direct risk signal in this population remains unknown. In a prospective cohort of 108 PD patients, standardized clinic BP was recorded at baseline with the validated device HEM-705 (Omron, Healthcare, Bannockburn, IL, USA) and 24-h ambulatory BP monitoring was performed using the Mobil-O-Graph monitor (IEM, Stolberg, Germany). Over a median follow-up of 16 months (interquartile range: 19 months), 47.2% of the overall population reached the composite outcome of non-fatal myocardial infarction, non-fatal stroke, or all-cause death. In Cox-regression analysis, systolic but not diastolic BP was prognostically informative. Compared with the reference quartile 1 of 24-h systolic BP (SBP), the multivariate-adjusted hazard ratio for the composite outcome was 1.098 (95% confidence interval (CI): 0.434–2.777) in quartile 2, 1.004 (95% CI: 0.382–2.235) in quartile 3 and 2.449 (95% CI: 1.156–5.190) in quartile 4. In contrast, no such association was observed between increasing quartiles of clinic SBP and composite outcome. The present study shows that among PD patients, increasing ambulatory SBP is independently associated with higher risk of adverse cardiovascular events and mortality, providing superior prognostic information than standardized clinic SBP.
Clinical Applications of Liquid Biopsy in Non-Small Cell Lung Cancer Patients: Current Status and Recent Advances in Clinical Practice
Authors: Park Shinhee , Lee Jae-Cheol , Choi Chang-Min
Published: May 2021

Recent advances in targeted and immune therapies have enabled tailored treatment strategies for advanced lung cancer. Identifying and understanding the genomic alterations that arise in the course of tumor evolution has become hugely valuable, but tissue biopsies are often insufficient for representing the whole cancer genome due to tumor heterogeneity. A liquid biopsy refers to the isolation and analysis of any tumor-derived material in the blood, and recent studies of this material have mostly focused on cell-free tumor DNA (ctDNA) in plasma. Indeed, liquid biopsy analysis is now expected to expand in utility and scope in clinical practice. In this review, we assess the biology and technical aspects of ctDNA analysis and discuss how it is currently applied in the clinic. Key points: Liquid biopsy is a potentially powerful tool in the era of personalized medicine for guiding targeted therapies in non-small cell lung cancer.
The Direct Anterior Approach to Primary Total Hip Replacement: Radiological Analysis in Comparison to Other Approaches
Authors: Stolarczyk Artur , Stolarczyk Magda , Stępiński Piotr , Dorocińska Monika K. , Świercz Maciej , Szymczak Jakub , Żarnovsky Krystian , Żuchniewicz Albert , Maciąg Bartosz M.
Published: May 2021

Total hip arthroplasty (THA) is currently considered the most effective treatment for end-stage hip osteoarthritis (OA). The surgery can be performed via a number of different approaches, including direct anterior (DAA; Smith–Petersen; Hueter), anterolateral (ALA; Watson–Jones), direct lateral (LA; Bauer), posterior (PA; Kocher–Langenbeck), and posterolateral (PLA). There is still a dispute over the optimal technique. The aim of this systematic review was to assess how different surgical approaches toward a THA influence the prosthesis elements’ positioning. We conducted a literature search of Scopus, ScienceDirect, PubMed, Embase, and The Cochrane Library. We evaluated studies in terms of the first author’s name, country, publication year, type of surgical approach being compared to the direct anterior approach, any significant differences at baseline, sample size, and radiographic analysis. A subanalysis of each approach in comparison to the DAA revealed differences in terms of all analyzed implant positioning radiographic parameters. There is still an insufficient number of randomized controlled studies that include radiological analyses comparing THRs (total hip replacements) performed using DAA with other approaches. Implant placement is a crucial step during a THR and surgeons must be aware that the approach they use might impact their judgment on angles and spaces inside the joint and thus alter the implant positioning.
Open Source Vacuum Oven Design for Low-Temperature Drying: Performance Evaluation for Recycled PET and Biomass
Authors: Hubbard Benjamin R. , Putman Lindsay I. , Techtmann Stephen , Pearce Joshua M.
Published: May 2021

Vacuum drying can dehydrate materials further than dry heat methods, while protecting sensitive materials from thermal degradation. Many industries have shifted to vacuum drying as cost- or time-saving measures. Small-scale vacuum drying, however, has been limited by the high costs of specialty scientific tools. To make vacuum drying more accessible, this study provides design and performance information for a small-scale open source vacuum oven, which can be fabricated from off-the-shelf and 3-D printed components. The oven is tested for drying speed and effectiveness on both waste plastic polyethylene terephthalate (PET) and a consortium of bacteria developed for bioprocessing of terephthalate wastes to assist in distributed recycling of PET for both additive manufacturing as well as potential food. Both materials can be damaged when exposed to high temperatures, making vacuum drying a desirable solution. The results showed that the open source vacuum oven was effective at drying both plastic and biomaterials, drying at a higher rate than a hot-air dryer for small samples or for low volumes of water. The system can be constructed for less than 20% of commercial vacuum dryer costs for several laboratory-scale applications, including dehydration of bio-organisms, drying plastic for distributed recycling and additive manufacturing, and chemical processing.
The Use of Living Mussels as a Substratum for Growing Seedlings of Two Sargassum Species from the Perspective of Coastal Seaweed Bed Restoration in the East China Sea
Authors: Li Xunmeng , Wang Kai , Feng Meiping , Chen Jianqu , Zhang Shouyu , Bi Yuanxin
Published: May 2021

Sargassum vachellianum and Sargassum horneri are the main dominant species and primary producers of seaweed beds in Chinese coastal ecosystems that play an important role in marine blue carbon sinks. However, due to the influence of frequent human activities and global climate change, the seaweed beds formed by Sargassum vachellianum and Sargassum horneri in Chinese coastal waters are gradually declining. In this study, Sargassum zygotes were cultured onto the surface of mussels and then used to repair the declining seaweed bed resources through seaweed transplantation, which was indirectly achieved based on the fast attachment of mussel byssus. The results show that zygotes of Sargassum vachellianum and Sargassum horneri could grow on the surface of mussels and, over time, the force and rate of mussel adhesion gradually increased. The adhesion of Mytilus coruscus was greater than that of Septifer virgatus mussels. After four hours, the rate of adhesion for Mytilus coruscus with a shell length of 30 mm was 100%, and the adhesion force was the highest, at 0.511 ± 0.099 N. Hence, Mytilus coruscus showed better adhesion than Septifer virgatus. After 41 days, the mean length of Sargassum horneri germlings on the surface of Mytilus coruscus grew to 5.554 ± 0.724 mm, the daily growth rate was about 0.154 mm/d, and the mean density declined by 50.59%. After 31 days, the mean length of Sargassum vachellianum germlings increased to 5.510 ± 0.763 mm, the daily growth rate was about 0.191 mm/d, and the mean density declined by 21.21%. After 2 months of development of the mussel–seaweed combinations in coastal waters, the survival rate of Sargassum horneri was 7.6 ± 0.9% and that of Sargassum vachellianum was 25.9 ± 10.5%. Hence, compared with Sargassum horneri, Sargassum vachellianum attached to Mytilus coruscus showed better development, and this system can be used to combat the decline in seaweed bed resources. In this method, mussels were used as an intermediate attachment medium to indirectly achieve the settlement of zygotes for seaweed transplantation, and, therefore, their use as a substratum serves as the basis for a novel technique for seaweed beds restoration.
Resistance to Echinocandins Complicates a Case of Candida albicans Bloodstream Infection: A Case Report
Authors: Trovato Laura , Bongiorno Dafne , Calvo Maddalena , Migliorisi Giuseppe , Boraccino Albino , Musso Nicolò , Oliveri Salvatore , Stefani Stefania , Scalia Guido
Published: May 2021

Invasive candidiasis is known to be one of the most common healthcare-associated complications and is caused by several Candida species. First-line drugs, particularly echinocandins, are effective, but there are increasing reports of resistance to these molecules, though rarely related to C. albicans. Even though the rate of echinocandins resistance remains low (<3%), sporadic cases are emerging. Here, we present a case of bloodstream infection by a pan-echinocandin-resistant Candida albicans affecting a critically ill patient, who died in an intensive care unit following therapeutic failure and multiple organ dysfunction syndrome. This case highlights the need to suspect pan-echinocandin resistance in patients with prolonged echinocandin exposure, particularly in the presence of urinary tract colonization. Our study shows the importance of sequencing to predict therapeutic failure in patients treated with echinocandins and persistent candidemia.
Application of Disinfectants for Environmental Control of a Lethal Amphibian Pathogen
Authors: Lammens Leni , Martel An , Pasmans Frank
Published: May 2021

Chytridiomycosis is an emerging infectious disease threatening amphibian populations worldwide. While environmental disinfection is important in mitigating the disease, successful elimination of Batrachochytrium dendrobatidis (Bd) without excessively harming ecosystems is challenging. We selected peracetic acid (PAA) as the most potent of six commercially available products regarding their ability to inhibit growth of a highly virulent Bd strain. PAA killed Bd after 5 min of exposure to approximately 94.7 mg/L. We examined the toxicity of PAA against three invertebrate species and Discoglossus pictus tadpoles. 93% of invertebrates, but none of the tadpoles survived 5 min of exposure to 94.7 mg/L. Tadpoles showed no adverse effects after 5 min exposure to concentrations of approximately 37.9 mg/L or lower. Addition of PAA to aquatic microcosms decreased pH, while dissolved oxygen (DO) initially increased. Degradation of PAA reversed the pH drop, but caused a massive drop in DO, which could be remedied by aeration. As proof of concept, microcosms that were aerated and treated with 94.7 mg/L PAA sustained survival of tadpoles starting 48 h after treatment. Disinfecting aquatic environments using PAA could contribute to mitigating chytridiomycosis, while preserving at least some invertebrate diversity, but requires temporary removal of resident amphibians.