bluuebunny/crossref_metadata_2025 huggingface dataset:
Tannylated Calcium Carbonate Materials with Antacid, Anti-Inflammatory, and Antioxidant Effects
Authors: Jung Sung-Yun , Hwang Heamin , Jo Han-Saem , Choi Somang , Kim Hak-Jun , Kim Sung-Eun , Park Kyeongsoon
Published: April 2021

Calcium carbonate (CaCO3)-based materials have received notable attention for biomedical applications owing to their safety and beneficial characteristics, such as pH sensitivity, carbon dioxide (CO2) gas generation, and antacid properties. Herein, to additionally incorporate antioxidant and anti-inflammatory functions, we prepared tannylated CaCO3 (TA-CaCO3) materials using a simple reaction between tannic acid (TA), calcium (Ca2+), and carbonate (CO32−) ions. TA-CaCO3 synthesized at a molar ratio of 1:75 (TA:calcium chloride (CaCl2)/sodium carbonate (Na2CO3)) showed 3–6 μm particles, comprising small nanoparticles in a size range of 17–41 nm. The TA-CaCO3 materials could efficiently neutralize the acid solution and scavenge free radicals. In addition, these materials could significantly reduce the mRNA levels of pro-inflammatory factors and intracellular reactive oxygen species, and protect chondrocytes from toxic hydrogen peroxide conditions. Thus, in addition to their antacid property, the prepared TA-CaCO3 materials exert excellent antioxidant and anti-inflammatory effects through the introduction of TA molecules. Therefore, TA-CaCO3 materials can potentially be used to treat inflammatory cells or diseases.
Emerging Emulsifiers: Conceptual Basis for the Identification and Rational Design of Peptides with Surface Activity
Authors: Ricardo Fabian , Pradilla Diego , Cruz Juan C. , Alvarez Oscar
Published: April 2021

Emulsifiers are gradually evolving from synthetic molecules of petrochemical origin to biomolecules mainly due to health and environmental concerns. Peptides represent a type of biomolecules whose molecular structure is composed of a sequence of amino acids that can be easily tailored to have specific properties. However, the lack of knowledge about emulsifier behavior, structure–performance relationships, and the implementation of different design routes have limited the application of these peptides. Some computational and experimental approaches have tried to close this knowledge gap, but restrictions in understanding the fundamental phenomena and the limited property data availability have made the performance prediction for emulsifier peptides an area of intensive research. This study provides the concepts necessary to understand the emulsifying behavior of peptides. Additionally, a straightforward description is given of how the molecular structure and conditions of the system directly impact the peptides’ ability to stabilize emulsion droplets. Moreover, the routes to design and discover novel peptides with interfacial and emulsifying activity are also discussed, along with the strategies to address some of their major pitfalls and challenges. Finally, this contribution reviews methodologies to build and use data sets containing standard properties of emulsifying peptides by looking at successful applications in different fields.
When the Balance Tips: Dysregulation of Mitochondrial Dynamics as a Culprit in Disease
Authors: Kyriakoudi Styliana , Drousiotou Anthi , Petrou Petros P.
Published: April 2021

Mitochondria are dynamic organelles, the morphology of which is tightly linked to their functions. The interplay between the coordinated events of fusion and fission that are collectively described as mitochondrial dynamics regulates mitochondrial morphology and adjusts mitochondrial function. Over the last few years, accruing evidence established a connection between dysregulated mitochondrial dynamics and disease development and progression. Defects in key components of the machinery mediating mitochondrial fusion and fission have been linked to a wide range of pathological conditions, such as insulin resistance and obesity, neurodegenerative diseases and cancer. Here, we provide an update on the molecular mechanisms promoting mitochondrial fusion and fission in mammals and discuss the emerging association of disturbed mitochondrial dynamics with human disease.
Regulatory Role of Sex Hormones in Cardiovascular Calcification
Authors: Woodward Holly J. , Zhu Dongxing , Hadoke Patrick W. F. , MacRae Victoria E.
Published: April 2021

Sex differences in cardiovascular disease (CVD), including aortic stenosis, atherosclerosis and cardiovascular calcification, are well documented. High levels of testosterone, the primary male sex hormone, are associated with increased risk of cardiovascular calcification, whilst estrogen, the primary female sex hormone, is considered cardioprotective. Current understanding of sexual dimorphism in cardiovascular calcification is still very limited. This review assesses the evidence that the actions of sex hormones influence the development of cardiovascular calcification. We address the current question of whether sex hormones could play a role in the sexual dimorphism seen in cardiovascular calcification, by discussing potential mechanisms of actions of sex hormones and evidence in pre-clinical research. More advanced investigations and understanding of sex hormones in calcification could provide a better translational outcome for those suffering with cardiovascular calcification.
In Vitro Evaluation of No-Carrier-Added Radiolabeled Cisplatin ([189, 191Pt]cisplatin) Emitting Auger Electrons
Authors: Obata Honoka , Tsuji Atsushi B. , Sudo Hitomi , Sugyo Aya , Minegishi Katsuyuki , Nagatsu Kotaro , Ogawa Mikako , Zhang Ming-Rong
Published: April 2021

Due to their short-range (2–500 nm), Auger electrons (Auger e−) have the potential to induce nano-scale physiochemical damage to biomolecules. Although DNA is the primary target of Auger e−, it remains challenging to maximize the interaction between Auger e− and DNA. To assess the DNA-damaging effect of Auger e− released as close as possible to DNA without chemical damage, we radio-synthesized no-carrier-added (n.c.a.) [189, 191Pt]cisplatin and evaluated both its in vitro properties and DNA-damaging effect. Cellular uptake, intracellular distribution, and DNA binding were investigated, and DNA double-strand breaks (DSBs) were evaluated by immunofluorescence staining of γH2AX and gel electrophoresis of plasmid DNA. Approximately 20% of intracellular radio-Pt was in a nucleus, and about 2% of intra-nucleus radio-Pt bound to DNA, although uptake of n.c.a. radio-cisplatin was low (0.6% incubated dose after 25-h incubation), resulting in the frequency of cells with γH2AX foci was low (1%). Nevertheless, some cells treated with radio-cisplatin had γH2AX aggregates unlike non-radioactive cisplatin. These findings suggest n.c.a. radio-cisplatin binding to DNA causes severe DSBs by the release of Auger e− very close to DNA without chemical damage by carriers. Efficient radio-drug delivery to DNA is necessary for successful clinical application of Auger e−.
Nuclear FGFR2 Interacts with the MLL-AF4 Oncogenic Chimera and Positively Regulates HOXA9 Gene Expression in t(4;11) Leukemia Cells
Authors: Fioretti Tiziana , Cevenini Armando , Zanobio Mariateresa , Raia Maddalena , Sarnataro Daniela , Cattaneo Fabio , Ammendola Rosario , Esposito Gabriella
Published: April 2021

The chromosomal translocation t(4;11) marks an infant acute lymphoblastic leukemia associated with dismal prognosis. This rearrangement leads to the synthesis of the MLL-AF4 chimera, which exerts its oncogenic activity by upregulating transcription of genes involved in hematopoietic differentiation. Crucial for chimera’s aberrant activity is the recruitment of the AF4/ENL/P-TEFb protein complex. Interestingly, a molecular interactor of AF4 is fibroblast growth factor receptor 2 (FGFR2). We herein analyze the role of FGFR2 in the context of leukemia using t(4;11) leukemia cell lines. We revealed the interaction between MLL-AF4 and FGFR2 by immunoprecipitation, western blot, and immunofluorescence experiments; we also tested the effects of FGFR2 knockdown, FGFR2 inhibition, and FGFR2 stimulation on the expression of the main MLL-AF4 target genes, i.e., HOXA9 and MEIS1. Our results show that FGFR2 and MLL-AF4 interact in the nucleus of leukemia cells and that FGFR2 knockdown, which is associated with decreased expression of HOXA9 and MEIS1, impairs the binding of MLL-AF4 to the HOXA9 promoter. We also show that stimulation of leukemia cells with FGF2 increases nuclear level of FGFR2 in its phosphorylated form, as well as HOXA9 and MEIS1 expression. In contrast, preincubation with the ATP-mimetic inhibitor PD173074, before FGF2 stimulation, reduced FGFR2 nuclear amount and HOXA9 and MEIS1 transcript level, thereby indicating that MLL-AF4 aberrant activity depends on the nuclear availability of FGFR2. Overall, our study identifies FGFR2 as a new and promising therapeutic target in t(4;11) leukemia.
Zebrafish Models to Study New Pathways in Tauopathies
Authors: Barbereau Clément , Cubedo Nicolas , Maurice Tangui , Rossel Mireille
Published: April 2021

Tauopathies represent a vast family of neurodegenerative diseases, the most well-known of which is Alzheimer’s disease. The symptoms observed in patients include cognitive deficits and locomotor problems and can lead ultimately to dementia. The common point found in all these pathologies is the accumulation in neural and/or glial cells of abnormal forms of Tau protein, leading to its aggregation and neurofibrillary tangles. Zebrafish transgenic models have been generated with different overexpression strategies of human Tau protein. These transgenic lines have made it possible to highlight Tau interacting factors or factors which may limit the neurotoxicity induced by mutations and hyperphosphorylation of the Tau protein in neurons. Several studies have tested neuroprotective pharmacological approaches. On few-days-old larvae, modulation of various signaling or degradation pathways reversed the deleterious effects of Tau mutations, mainly hTauP301L and hTauA152T. Live imaging and live tracking techniques as well as behavioral follow-up enable the analysis of the wide range of Tau-related phenotypes from synaptic loss to cognitive functional consequences.
The Challenge of Diagnosing Constitutional Mismatch Repair Deficiency Syndrome in Brain Malignancies from Young Individuals
Authors: Carrato Cristina , Sanz Carolina , Muñoz-Mármol Ana María , Blanco Ignacio , Pineda Marta , Del Valle Jesús , Dámaso Estela , Esteller Manel , Musulen Eva
Published: April 2021

Biallelic germline mismatch repair (MMR) gene (MLH1, MSH2, MSH6, and PMS2) mutations are an extremely rare event that causes constitutional mismatch repair deficiency (CMMRD) syndrome. CMMRD is underdiagnosed and often debuts with pediatric malignant brain tumors. A high degree of clinical awareness of the CMMRD phenotype is needed to identify new cases. Immunohistochemical (IHC) assessment of MMR protein expression and analysis of microsatellite instability (MSI) are the first tools with which to initiate the study of this syndrome in solid malignancies. MMR IHC shows a hallmark pattern with absence of staining in both neoplastic and non-neoplastic cells for the biallelic mutated gene. However, MSI often fails in brain malignancies. The aim of this report is to draw attention to the peculiar IHC profile that characterizes CMMRD syndrome and to review the difficulties in reaching an accurate diagnosis by describing the case of two siblings with biallelic MSH6 germline mutations and brain tumors. Given the difficulties involved in early diagnosis of CMMRD we propose the use of the IHC of MMR proteins in all malignant brain tumors diagnosed in individuals younger than 25 years-old to facilitate the diagnosis of CMMRD and to select those neoplasms that will benefit from immunotherapy treatment.
Identification and Characterization of Abiotic Stress Responsive CBL-CIPK Family Genes in Medicago
Authors: Du Wenxuan , Yang Junfeng , Ma Lin , Su Qian , Pang Yongzhen
Published: April 2021

The calcineurin B-like protein (CBL) and CBL-interacting protein kinase (CIPK) play important roles in plant signal transduction and response to abiotic stress. Plants of Medicago genus contain many important forages, and their growth is often affected by a variety of abiotic stresses. However, studies on the CBL and CIPK family member and their function are rare in Medicago. In this study, a total of 23 CBL and 58 CIPK genes were identified from the genome of Medicago sativa as an important forage crop, and Medicaog truncatula as the model plant. Phylogenetic analysis suggested that these CBL and CIPK genes could be classified into five and seven groups, respectively. Moreover, these genes/proteins showed diverse exon-intron organizations, architectures of conserved protein motifs. Many stress-related cis-acting elements were found in their promoter region. In addition, transcriptional analyses showed that these CBL and CIPK genes exhibited distinct expression patterns in various tissues, and in response to drought, salt, and abscisic acid treatments. In particular, the expression levels of MtCIPK2 (MsCIPK3), MtCIPK17 (MsCIPK11), and MtCIPK18 (MsCIPK12) were significantly increased under PEG, NaCl, and ABA treatments. Collectively, our study suggested that CBL and CIPK genes play crucial roles in response to various abiotic stresses in Medicago.
Examination of Surfactant Protein D as a Biomarker for Evaluating Pulmonary Toxicity of Nanomaterials in Rat
Authors: Tomonaga Taisuke , Izumi Hiroto , Yoshiura Yukiko , Nishida Chinatsu , Yatera Kazuhiro , Morimoto Yasuo
Published: April 2021

This work studies the relationship between lung inflammation caused by nanomaterials and surfactant protein D (SP-D) kinetics and investigates whether SP-D can be a biomarker of the pulmonary toxicity of nanomaterials. Nanomaterials of nickel oxide and cerium dioxide were classified as having high toxicity, nanomaterials of two types of titanium dioxides and zinc oxide were classified as having low toxicity, and rat biological samples obtained from 3 days to 6 months after intratracheal instillation of those nanomaterials and micron-particles of crystalline silica were used. There were different tendencies of increase between the high- and low-toxicity materials in the concentration of SP-D in bronchoalveolar-lavage fluid (BALF) and serum and in the expression of the SP-D gene in the lung tissue. An analysis of the receiver operating characteristics for the toxicity of the nanomaterials by SP-D in BALF and serum showed a high accuracy of discrimination from 1 week to 3 or 6 months after exposure. These data suggest that the differences in the expression of SP-D in BALF and serum depended on the level of lung inflammation caused by the nanomaterials and that SP-D can be biomarkers for evaluating the pulmonary toxicity of nanomaterials.
Effect of Soluble Adenylyl Cyclase (ADCY10) Inhibitors on the LH-Stimulated cAMP Synthesis in Mltc-1 Leydig Cell Line
Authors: Nguyen Thi Mong Diep , Filliatreau Laura , Klett Danièle , Hai Nong Van , Duong Nguyen Thuy , Combarnous Yves
Published: April 2021

In contrast to all transmembrane adenylyl cyclases except ADCY9, the cytosolic soluble adenylyl cyclase (ADCY10) is insensitive to forskolin stimulation and is uniquely modulated by calcium and bicarbonate ions. In the present paper, we focus on ADCY10 localization and a kinetic analysis of intracellular cAMP accumulation in response to human LH in the absence or presence of four different ADCY10 inhibitors (KH7, LRE1, 2-CE and 4-CE) in MTLC-1 cells. ADCY10 was immuno-detected in the cytoplasm of MLTC-1 cells and all four inhibitors were found to inhibit LH-stimulated cAMP accumulation and progesterone level in MLTC-1 and testosterone level primary Leydig cells. Interestingly, similar inhibitions were also evidenced in mouse testicular Leydig cells. In contrast, the tmAC-specific inhibitors ddAdo3′ and ddAdo5′, even at high concentration, exerted weak or no inhibition on cAMP accumulation, suggesting an important role of ADCY10 relative to tmACs in the MLTC-1 response to LH. The strong synergistic effect of HCO3− under LH stimulation further supports the involvement of ADCY10 in the response to LH.
Myocardial Hypertrophy and Fibrosis Are Associated with Cardiomyocyte Beta-Catenin and TRPC6/Calcineurin/NFAT Signaling in Spontaneously Hypertensive Rats with 5/6 Nephrectomy
Authors: Bogdanova Evdokia , Beresneva Olga , Galkina Olga , Zubina Irina , Ivanova Galina , Parastaeva Marina , Semenova Natalia , Dobronravov Vladimir
Published: April 2021

Background: Arterial hypertension (AH) is associated with heart and chronic kidney disease (CKD). However, the precise mechanisms of myocardial remodeling (MR) in the settings of CKD remain elusive. We hypothesized that TRPC6, calcineurin/NFAT, and Wnt/β-catenin signaling pathways are involved in the development of MR in the background of CKD and AH. Methods: Early CKD was induced by performing a 5/6 nephrectomy (5/6NE) in spontaneously hypertensive rats (SHR-NE). Sham-operated (SO) SHR (SHR-SO) and Wistar Kyoto (WKY-SO) rats served as controls. Systolic blood pressure (SBP), heart rate, myocardial mass index (MMI), serum creatinine, cardiomyocyte diameter (dCM), myocardial fibrosis (MF), serum and kidney α-Klotho levels, myocardial expression of calcineurin (CaN), TRPC6, and β-catenin were measured two months after 5/6NE or SO. Results: NE-induced kidney dysfunction corresponded to mild-to-moderate human CKD and was associated with an increase in FGF23 and a decrease in renal α-Klotho. The levels of SBP, MMI, dCM, and MF were higher in SHRs compared to WKY-SO as well as in SHR-NE vs. SHR-SO. The MR was associated with increased cardiomyocyte expression of CaN/NFAT and β-catenin along with its intracellular re-distribution. TRPC6 protein levels were substantially elevated in both SHR groups with higher Trpc6 mRNA expression in SHR-NE. Conclusions: The Wnt/β-catenin and TRPC6/CaN/NFAT hypertrophic signaling pathways seem to be involved in myocardial remodeling in the settings of AH and CKD and might be mediated by FGF23 and α-Klotho axis.
Connection between Periodontitis-Induced Low-Grade Endotoxemia and Systemic Diseases: Neutrophils as Protagonists and Targets
Authors: Vitkov Ljubomir , Muñoz Luis E. , Knopf Jasmin , Schauer Christine , Oberthaler Hannah , Minnich Bernd , Hannig Matthias , Herrmann Martin
Published: April 2021

Periodontitis is considered a promoter of many systemic diseases, but the signaling pathways of this interconnection remain elusive. Recently, it became evident that certain microbial challenges promote a heightened response of myeloid cell populations to subsequent infections either with the same or other pathogens. This phenomenon involves changes in the cell epigenetic and transcription, and is referred to as ‘‘trained immunity’’. It acts via modulation of hematopoietic stem and progenitor cells (HSPCs). A main modulation driver is the sustained, persistent low-level transmission of lipopolysaccharide from the periodontal pocket into the peripheral blood. Subsequently, the neutrophil phenotype changes and neutrophils become hyper-responsive and prone to boosted formation of neutrophil extracellular traps (NET). Cytotoxic neutrophil proteases and histones are responsible for ulcer formations on the pocket epithelium, which foster bacteremia and endoxemia. The latter promote systemic low-grade inflammation (SLGI), a precondition for many systemic diseases and some of them, e.g., atherosclerosis, diabetes etc., can be triggered by SLGI alone. Either reverting the polarized neutrophils back to the homeostatic state or attenuation of neutrophil hyper-responsiveness in periodontitis might be an approach to diminish or even to prevent systemic diseases.
Inhibition of β-Catenin Activity Abolishes LKB1 Loss-Driven Pancreatic Cystadenoma in Mice
Authors: Hsieh Mei-Jen , Weng Ching-Chieh , Lin Yu-Chun , Wu Chia-Chen , Chen Li-Tzong , Cheng Kuang-Hung
Published: April 2021

Pancreatic cancer (PC) is the seventh leading cause of cancer death worldwide, and remains one of our most recalcitrant and dismal diseases. In contrast to many other malignancies, there has not been a significant improvement in patient survival over the past decade. Despite advances in our understanding of the genetic alterations associated with this disease, an incomplete understanding of the underlying biology and lack of suitable animal models have hampered efforts to develop more effective therapies. LKB1 is a tumor suppressor that functions as a primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK), which is an important mediator in the regulation of cell growth and epithelial polarity pathways. LKB1 is mutated in a significant number of Peutz–Jeghers syndrome (PJS) patients and in a small proportion of sporadic cancers, including PC; however, little is known about how LKB1 loss contributes to PC development. Here, we report that a reduction in Wnt/β-catenin activity is associated with LKB1 tumor-suppressive properties in PC. Remarkably, in vivo functional analyses of β-catenin in the Pdx-1-Cre LKB1L/L β-cateninL/L mouse model compared to LKB1 loss-driven cystadenoma demonstrate that the loss of β-catenin impairs cystadenoma development in the pancreas of Pdx-1Cre LKB1L/L mice and dramatically restores the normal development and functions of the pancreas. This study further determined the in vivo and in vitro therapeutic efficacy of the β-catenin inhibitor FH535 in suppressing LKB1 loss-driven cystadenoma and reducing PC progression that delineates the potential roles of Wnt/β-catenin signaling in PC harboring LKB1 deficiency.
Potential Antitumor Effects of 6-Gingerol in p53-Dependent Mitochondrial Apoptosis and Inhibition of Tumor Sphere Formation in Breast Cancer Cells
Authors: Sp Nipin , Kang Dong Young , Lee Jin-Moo , Bae Se Won , Jang Kyoung-Jin
Published: April 2021

Hormone-specific anticancer drugs for breast cancer treatment can cause serious side effects. Thus, treatment with natural compounds has been considered a better approach as this minimizes side effects and has multiple targets. 6-Gingerol is an active polyphenol in ginger with various modalities, including anticancer activity, although its mechanism of action remains unknown. Increases in the level of reactive oxygen species (ROS) can lead to DNA damage and the induction of DNA damage response (DDR) mechanism, leading to cell cycle arrest apoptosis and tumorsphere suppression. Epidermal growth factor receptor (EGFR) promotes tumor growth by stimulating signaling of downstream targets that in turn activates tumor protein 53 (p53) to promote apoptosis. Here we assessed the effect of 6-gingerol treatment on MDA-MB-231 and MCF-7 breast cancer cell lines. 6-Gingerol induced cellular and mitochondrial ROS that elevated DDR through ataxia-telangiectasia mutated and p53 activation. 6-Gingerol also induced G0/G1 cell cycle arrest and mitochondrial apoptosis by mediating the BAX/BCL-2 ratio and release of cytochrome c. It also exhibited a suppression ability of tumorsphere formation in breast cancer cells. EGFR/Src/STAT3 signaling was also determined to be responsible for p53 activation and that 6-gingerol induced p53-dependent intrinsic apoptosis in breast cancer cells. Therefore, 6-gingerol may be used as a candidate drug against hormone-dependent breast cancer cells.
Genome-Wide Investigation of the NF-X1 Gene Family in Populus trichocarpa Expression Profiles during Development and Stress
Authors: He Fang , Shi Yu-Jie , Mi Jia-Xuan , Zhao Kuang-Ji , Cui Xing-Lei , Chen Liang-Hua , Yang Han-Bo , Zhang Fan , Zhao Qian , Huang Jin-Liang , Wan Xue-Qin
Published: April 2021

Poplar are planted extensively in reforestation and afforestation. However, their successful establishment largely depends on the environmental conditions of the newly established plantation and their resistance to abiotic as well as biotic stresses. NF-X1, a widespread transcription factor in plants, plays an irreplaceable role in plant growth, development, and stress tolerance. Although the whole genome sequence of Populus trichocarpa has been published for a long time, little is known about the NF-X1 genes in poplar, especially those related to drought stress, mechanical damage, insect feeding, and hormone response at the whole genome level. In this study, whole genome analysis of the poplar NF-X1 family was performed, and 4 PtrNF-X1 genes were identified. Then, bioinformatics analysis and qRT-PCR were applied to analyze the gene structure, phylogeny, chromosomal localization, gene replication, Cis-elements, and expression patterns of PtrNF-X1genes. Sequence analysis revealed that one-quarter of the PtrNF-X1 genes did not contain introns. Phylogenetic analysis revealed that all NF-X1 genes were split into three subfamilies. The number of two pairs of segmented replication genes were detected in poplars. Cis-acting element analysis identified a large number of elements of growth and development and stress-related elements on the promoters of different NF-X1 members. In addition, some PtrNF-X1 could be significantly induced by polyethylene glycol (PEG) and abscisic acid (ABA), thus revealing their potential role in regulating stress response. Comprehensive analysis is helpful in selecting candidate NF-X1 genes for the follow-up study of the biological function, and molecular genetic progress of stress resistance in forest trees provides genetic resources.
The Novel Role of PGC1α in Bone Metabolism
Authors: Buccoliero Cinzia , Dicarlo Manuela , Pignataro Patrizia , Gaccione Francesco , Colucci Silvia , Colaianni Graziana , Grano Maria
Published: April 2021

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that PGC1α deletion negatively affects cortical thickness, trabecular organization and resistance to flexion, resulting in increased risk of fracture. Furthermore, in a mouse model of bone disease, PGC1α activation stimulates osteoblastic gene expression and inhibits atrogene transcription. PGC1α overexpression positively affects the activity of Sirtuin 3, a mitochondrial nicotinammide adenina dinucleotide (NAD)-dependent deacetylase, on osteoblastic differentiation. In vitro, PGC1α overexpression prevents the reduction of mitochondrial density, membrane potential and alkaline phosphatase activity caused by Sirtuin 3 knockdown in osteoblasts. Moreover, PGC1α influences the commitment of skeletal stem cells towards an osteogenic lineage, while negatively affects marrow adipose tissue accumulation. In this review, we will focus on recent findings about PGC1α action on bone metabolism, in vivo and in vitro, and in pathologies that cause bone loss, such as osteoporosis and type 2 diabetes.
The Neuroprotective Effects of GPR4 Inhibition through the Attenuation of Caspase Mediated Apoptotic Cell Death in an MPTP Induced Mouse Model of Parkinson’s Disease
Authors: Haque Md Ezazul , Azam Shofiul , Akther Mahbuba , Cho Duk-Yeon , Kim In-Su , Choi Dong-Kug
Published: April 2021

The proton-activated G protein-coupled receptor (GPCR) 4 (GPR4) is constitutively active at physiological pH, and GPR4 knockout protected dopaminergic neurons from caspase-dependent mitochondria-associated apoptosis. This study explored the role of GPR4 in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson’s disease (PD). In mice, subchronic MPTP administration causes oxidative stress-induced apoptosis in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), resulting in motor deficits. NE52-QQ57, a selective GPR4 antagonist, reduced dopaminergic neuronal loss in MPTP-treated mice, improving motor and memory functions. MPTP and NE52-QQ57 co-treatment in mice significantly decreased pro-apoptotic marker Bax protein levels and increased anti-apoptotic marker Bcl-2 protein levels in the SNpc and striatum. MPTP-induced caspase 3 activation and poly (ADP-ribose) polymerase (PARP) cleavage significantly decreased in the SNpc and striatum of mice co-treated with NE52-QQ57. MPTP and NE52-QQ57 co-treatment significantly increased tyrosine hydroxylase (TH)-positive cell numbers in the SNpc and striatum compared with MPTP alone. NE52-QQ57 and MPTP co-treatment improved rotarod and pole test–assessed motor performance and improved Y-maze test–assessed spatial memory. Our findings suggest GPR4 may represent a potential therapeutic target for PD, and GPR4 activation is involved in caspase-mediated neuronal apoptosis in the SNpc and striatum of MPTP-treated mice.
The Contribution of Microglia to Neuroinflammation in Parkinson’s Disease
Authors: Badanjak Katja , Fixemer Sonja , Smajić Semra , Skupin Alexander , Grünewald Anne
Published: April 2021

With the world’s population ageing, the incidence of Parkinson’s disease (PD) is on the rise. In recent years, inflammatory processes have emerged as prominent contributors to the pathology of PD. There is great evidence that microglia have a significant neuroprotective role, and that impaired and over activated microglial phenotypes are present in brains of PD patients. Thereby, PD progression is potentially driven by a vicious cycle between dying neurons and microglia through the instigation of oxidative stress, mitophagy and autophagy dysfunctions, a-synuclein accumulation, and pro-inflammatory cytokine release. Hence, investigating the involvement of microglia is of great importance for future research and treatment of PD. The purpose of this review is to highlight recent findings concerning the microglia-neuronal interplay in PD with a focus on human postmortem immunohistochemistry and single-cell studies, their relation to animal and iPSC-derived models, newly emerging technologies, and the resulting potential of new anti-inflammatory therapies for PD.
Nod-Like Receptors in Host Defence and Disease at the Epidermal Barrier
Authors: Danis Judit , Mellett Mark
Published: April 2021

The nucleotide-binding domain and leucine-rich-repeat-containing family (NLRs) (sometimes called the NOD-like receptors, though the family contains few bona fide receptors) are a superfamily of multidomain-containing proteins that detect cellular stress and microbial infection. They constitute a critical arm of the innate immune response, though their functions are not restricted to pathogen recognition and members engage in controlling inflammasome activation, antigen-presentation, transcriptional regulation, cell death and also embryogenesis. NLRs are found from basal metazoans to plants, to zebrafish, mice and humans though functions of individual members can vary from species to species. NLRs also display highly wide-ranging tissue expression. Here, we discuss the importance of NLRs to the immune response at the epidermal barrier and summarise the known role of individual family members in the pathogenesis of skin disease.
Face Recognition Based on Lightweight Convolutional Neural Networks
Authors: Liu Wenting , Zhou Li , Chen Jie
Published: April 2021

Face recognition algorithms based on deep learning methods have become increasingly popular. Most of these are based on highly precise but complex convolutional neural networks (CNNs), which require significant computing resources and storage, and are difficult to deploy on mobile devices or embedded terminals. In this paper, we propose several methods to improve the algorithms for face recognition based on a lightweight CNN, which is further optimized in terms of the network architecture and training pattern on the basis of MobileFaceNet. Regarding the network architecture, we introduce the Squeeze-and-Excitation (SE) block and propose three improved structures via a channel attention mechanism—the depthwise SE module, the depthwise separable SE module, and the linear SE module—which are able to learn the correlation of information between channels and assign them different weights. In addition, a novel training method for the face recognition task combined with an additive angular margin loss function is proposed that performs the compression and knowledge transfer of the deep network for face recognition. Finally, we obtained high-precision and lightweight face recognition models with fewer parameters and calculations that are more suitable for applications. Through extensive experiments and analysis, we demonstrate the effectiveness of the proposed methods.
The Essential and Enigmatic Role of ABC Transporters in Bt Resistance of Noctuids and Other Insect Pests of Agriculture
Authors: Heckel David G.
Published: April 2021

In the last ten years, ABC transporters have emerged as unexpected yet significant contributors to pest resistance to insecticidal pore-forming proteins from Bacillus thuringiensis (Bt). Evidence includes the presence of mutations in resistant insects, heterologous expression to probe interactions with the three-domain Cry toxins, and CRISPR/Cas9 knockouts. Yet the mechanisms by which ABC transporters facilitate pore formation remain obscure. The three major classes of Cry toxins used in agriculture have been found to target the three major classes of ABC transporters, which requires a mechanistic explanation. Many other families of bacterial pore-forming toxins exhibit conformational changes in their mode of action, which are not yet described for the Cry toxins. Three-dimensional structures of the relevant ABC transporters, the multimeric pore in the membrane, and other proteins that assist in the process are required to test the hypothesis that the ATP-switch mechanism provides a motive force that drives Cry toxins into the membrane. Knowledge of the mechanism of pore insertion will be required to combat the resistance that is now evolving in field populations of insects, including noctuids.
Mating Disruption for Managing the Honeydew Moth, Cryptoblabes gnidiella (Millière), in Mediterranean Vineyards
Authors: Ricciardi Renato , Di Giovanni Filippo , Cosci Francesca , Ladurner Edith , Savino Francesco , Iodice Andrea , Benelli Giovanni , Lucchi Andrea
Published: April 2021

The demand for a reduced use of pesticides in agriculture requires the development of specific strategies for managing arthropod pests. Among eco-friendly pest control tools, pheromone-based mating disruption (MD) is promising for controlling several key insect pests of economic importance, including many lepidopteran species. In our study, we evaluated an MD approach for managing the honeydew moth (HM), Cryptoblabes gnidiella, an emerging threat for the grapevine in the Mediterranean basin. The trials were carried out in two study sites, located in Tuscany (central Italy, years 2017–2019) and Apulia (southern Italy, years 2016 and 2018–2019), and by applying MD dispensers only in April, in April and July, and only in July. To evaluate the effects of MD, infested bunches (%), damaged area (%) per bunch, and number of living larvae per bunch were compared among plots covered with MD dispensers, insecticide-treated plots (Apulia only), and untreated control plots. Male flights were monitored using pheromone-baited sticky traps. Except for the sampling carried out in Tuscany in 2018, where HM infestation level was very low, a significant difference was recorded between MD and control plots, both in terms of HM damage caused to ripening grapes and/or number of living larvae per bunch. Overall, our study highlighted that MD, irrespective of the application timing, significantly reduced HM damage; the levels of control achieved here were similar to those obtained with the application of insecticides (no MD). However, MD used as stand-alone strategy was not able to provide complete pest control, which may instead be pursued by growers with an IPM approach.
The Comparison of Outcomes of Transvaginal Mesh Surgery with and without Midline Fascial Plication for the Treatment of Anterior Vaginal Prolapse: A Randomized Controlled Trial
Authors: Chiang Ching-Hsiang , Hsu Chun-Shuo , Ding Dah-Ching
Published: April 2021

The aim of this study was to compare the clinical outcomes of transvaginal mesh (TVM) surgery with and without midline fascial plication for anterior prolapse repair. This is a prospective randomized trial in a teaching hospital. This study compared patients with anterior vaginal wall prolapse (POP-Q Ba > −1) who were randomly assigned to either transvaginal mesh (TVM, Avaulta SoloTM, CR Bard. Inc., Covington, GA, USA polypropylene mesh delivery system) (group A, n = 32) or TVM with concomitant midline fascial plication (group B, n = 32). The outcomes of anatomy correction and life quality were evaluated using a pelvic organ prolapse quantification system and questionnaires. Sixty-four patients were included from January 2011 through April 2014 in this study. Group A had a mean age of 63.7 years and a body mass index (BMI) of 25.4 kg/m2. Group B had a mean age of 62.9 years and a BMI of 25.4. The mean follow-up duration was 18.6 months (range 12–50). At the 12-month follow-up, anatomic recurrence was higher in Group A (5/31, 16.1%) than in Group B (1/30, 3.3%) but without statistical significance (p = 0.19). Improvements in symptoms and quality of life were not significantly different between the two groups. Mesh extrusion was detected in three of 61 patients (4.9%): two from group A (6.7%) and one from Group B (3.2%). TVM with concomitant midline fascia repair for anterior vaginal prolapse had a comparable anterior support and mesh exposure rate compared with TVM alone. Trial Registration: IRB-B09904021
Participation in Social Activities and Relationship between Walking Habits and Disability Incidence
Authors: Katayama Osamu , Lee Sangyoon , Bae Seongryu , Makino Keitaro , Chiba Ippei , Harada Kenji , Shinkai Yohei , Shimada Hiroyuki
Published: April 2021

Identifying the relationship between physical and social activity and disability among community-dwelling older adults may provide important information for implementing tailored interventions to prevent disability progression. The aim of this study was to determine the effect of the number of social activities on the relationship between walking habits and disability incidence in older adults. We included 2873 older adults (mean age, 73.1 years; SD, ±5.9 years) from the National Center for Geriatrics and Gerontology—Study of Geriatric Syndromes. Baseline measurements, including frequencies of physical and social activities, health conditions, physical function, cognitive function, metabolic parameters, and other potential disability risk factors (for example, the number of years of education); monthly assessment for disability was monitored through long-term care insurance certification for at least 2 years from baseline. During a mean follow-up of 35.1 months (SD, 6.4 months), 133 participants developed disability. The disability incidence was 19.0 and 27.9 per 1000 person-years for participants who walked more (≥3 times per week) and less (≤3 times per week) frequently, respectively. The potential confounding factor-adjusted disability hazard ratio was 0.67 (95% confidence interval, 0.46 to 0.96; p = 0.030). The relationship between habitual walking and the number of social activities was statistically significant (p = 0.004). The reduction of disability risk by walking was greater among participants with fewer social activities. Habitual walking was associated with disability incidence, with a more pronounced effect among older adults who were less likely to engage in social activities.
Advanced Microscopy for Liver and Gut Ultrastructural Pathology in Patients with MVID and PFIC Caused by MYO5B Mutations
Authors: Hess Michael W. , Krainer Iris M. , Filipek Przemyslaw A. , Witting Barbara , Gutleben Karin , Vietor Ilja , Zoller Heinz , Aldrian Denise , Sturm Ekkehard , Goldenring James R. , Janecke Andreas R. , Müller Thomas , Huber Lukas A. , Vogel Georg F.
Published: April 2021

Mutations in the actin motor protein myosinVb (myo5b) cause aberrant apical cargo transport and the congenital enteropathy microvillus inclusion disease (MVID). Recently, missense mutations in myo5b were also associated with progressive familial intrahepatic cholestasis (MYO5B-PFIC). Here, we thoroughly characterized the ultrastructural and immuno-cytochemical phenotype of hepatocytes and duodenal enterocytes from a unique case of an adult MYO5B-PFIC patient who showed constant hepatopathy but only periodic enteric symptoms. Selected data from two other patients supported the findings. Advanced methods such as cryo-fixation, freeze-substitution, immuno-gold labeling, electron tomography and immuno-fluorescence microscopy complemented the standard procedures. Liver biopsies showed mislocalization of Rab11 and bile canalicular membrane proteins. Rab11-positive vesicles clustered around bile canaliculi and resembled subapical clusters of aberrant recycling endosomes in enterocytes from MVID patients. The adult patient studied in detail showed a severe, MVID-specific enterocyte phenotype, despite only a mild clinical intestinal presentation. This included mislocalization of numerous proteins essential for apical cargo transport and morphological alterations. We characterized the heterogeneous population of large catabolic organelles regarding their complex ultrastructure and differential distribution of autophagic and lysosomal marker proteins. Finally, we generated duodenal organoids/enteroids from biopsies that recapitulated all MVID hallmarks, demonstrating the potential of this disease model for personalized medicine.
Facial Affect Recognition by Patients with Schizophrenia Using Human Avatars
Authors: Muros Nora I. , García Arturo S. , Forner Cristina , López-Arcas Pablo , Lahera Guillermo , Rodriguez-Jimenez Roberto , Nieto Karen N. , Latorre José Miguel , Fernández-Caballero Antonio , Fernández-Sotos Patricia
Published: April 2021

People with schizophrenia have difficulty recognizing the emotions in the facial expressions of others, which affects their social interaction and functioning in the community. Static stimuli such as photographs have been used traditionally to examine deficiencies in the recognition of emotions in patients with schizophrenia, which has been criticized by some authors for lacking the dynamism that real facial stimuli have. With the aim of overcoming these drawbacks, in recent years, the creation and validation of virtual humans has been developed. This work presents the results of a study that evaluated facial recognition of emotions through a new set of dynamic virtual humans previously designed by the research team, in patients diagnosed of schizophrenia. The study included 56 stable patients, compared with 56 healthy controls. Our results showed that patients with schizophrenia present a deficit in facial affect recognition, compared to healthy controls (average hit rate 71.6% for patients vs 90.0% for controls). Facial expressions with greater dynamism (compared to less dynamic ones), as well as those presented from frontal view (compared to profile view) were better recognized in both groups. Regarding clinical and sociodemographic variables, the number of hospitalizations throughout life did not correlate with recognition rates. There was also no correlation between functioning or quality of life and recognition. A trend showed a reduction in the emotional recognition rate as a result of increases in Positive and Negative Syndrome Scale (PANSS), being statistically significant for negative PANSS. Patients presented a learning effect during the progression of the task, slightly greater in comparison to the control group. This finding is relevant when designing training interventions for people with schizophrenia. Maintaining the attention of patients and getting them to improve in the proposed tasks is a challenge for today’s psychiatry.
The Holistic Coronary Physiology Display: Calculation of the Flow Separation Index in Vessel-Specific Individual Flow Range during Fractional Flow Reserve Measurement Using 3D Coronary Reconstruction
Authors: Szabó Gábor Tamás , Üveges Áron , Tar Balázs , Ágoston András , Dorj Azzaya , Jenei Csaba , Kolozsvári Rudolf , Csippa Benjamin , Czuriga Dániel , Kőszegi Zsolt
Published: April 2021

In order to make optimal decisions on the treatment of atherosclerotic coronary heart disease (CHD), appropriate evaluation is necessary, including both the anatomical and physiological assessment of the coronary arteries. According to current guidelines, a fractional flow reserve (FFR)–based clinical decision is recommended, but coronary flow reserve (CFR) measurements and microvascular evaluation should also be considered in special cases for a detailed exploration of the coronary disease state. We aimed to generate an extended physiological evaluation during routine FFR measurement and define a new pathological flow–related prognostic factor. Fluid dynamic equations were applied to calculate CFR on the basis of the three-dimensional (3D) reconstruction of the invasively acquired coronary angiogram and the measured intracoronary pressure data. A new, potentially robust prognostic parameter of a coronary lesion called the “flow separation index” (FSi), which is thought to detect the pathological flow amount through a stenosis was introduced in a vessel-specific flow range. Correlations between FSi and the clinically established physiological indices (CFR and FFR) were determined. The FSi was calculated in 19 vessels of 16 patients, including data from the pre- and post-stent revascularization treatment of 3 patients. There was no significant correlation between the FSi and the CFR (r = −0.23, p = 0.34); however, there was significant negative correlation between the FSi and the FFR (r = −0.66, p = 0.002). An even stronger correlation was found between the FSi and the ratio of the resting pressure ratio and the FFR (r = 0.92, p < 0.0001). The diagnostic power of the FSi for predicting the FFR value of <0.80, as a gold standard prognostic factor, was tested by receiver operating characteristic analysis. FSi > 0.022 proved to be the cutoff value of the prediction of a pathologically low FFR with a 0.856 area under the curve (95% confidence interval: 0.620 to 0.972). The present flow–pressure–velocity display provides a comprehensive summary of patient-specific pathophysiology in CHD. The consequences of epicardial stenoses can be evaluated together with their complex relations to microvascular conditions. Based on these values, clinical decision-making concerning both pharmacological therapy and percutaneous or surgical revascularization may be more precisely guided.
Imaging Predictive Factors of Abdominal Aortic Aneurysm Growth
Authors: Nana Petroula , Spanos Konstantinos , Dakis Konstantinos , Brodis Alexandros , Kouvelos George
Published: April 2021

Background: Variable imaging methods may add important information about abdominal aortic aneurysm (AAA) progression. The aim of this study is to assess available literature data regarding the predictive imaging factors of AAA growth. Methods: This systematic review was conducted using the PRISMA guidelines. A review of the literature was conducted, using PubMed, EMBASE and CENTRAL databases. The quality of the studies was assessed using the Newcastle-Ottawa Scale. Primary outcomes were defined as AAA growth rate and factors associated to sac expansion. Results: The analysis included 23 studies. All patients (2244; mean age; 69.8 years, males; 85%) underwent imaging with different modalities; the initial evaluation was followed by one or more studies to assess aortic expansion. AAA initial diameter was reported in 13 studies (range 19.9–50.9 mm). Mean follow-up was 34.5 months. AAA diameter at the end was ranging between 20.3 and 55 mm. The initial diameter and intraluminal thrombus were characterized as prognostic factors associated to aneurysm expansion. A negative association between atherosclerosis and AAA expansion was documented. Conclusions: Aneurysm diameter is the most studied factor to be associated with expansion and the main indication for intervention. Appropriate diagnostic modalities may account for different anatomical characteristics and identify aneurysms with rapid growth and higher rupture risk. Future perspectives, including computed mathematical models that will assess wall stress and elasticity and further flow characteristics, may offer valuable alternatives in AAA growth prediction.