bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of the IL-18 Receptor Signaling Pathway Ameliorates Disease in a Murine Model of Rheumatoid Arthritis
Authors: Nozaki Yuji , Ri Jinhai , Sakai Kenji , Niki Kaoru , Kinoshita Koji , Funauchi Masanori , Matsumura Itaru
Published: December 2019

Interleukin (IL)-18 expression in synovial tissue correlates with the severity of joint inflammation and the levels of pro-inflammatory cytokines. However, the role of the IL-18/IL-18 receptor-alpha (Rα) signaling pathway in autoimmune arthritis is unknown. Wild-type (WT) and IL-18Rα knockout (KO) mice were immunized with bovine type II collagen before the onset of arthritis induced by lipopolysaccharide injection. Disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum inflammatory cytokine and anticollagen antibody levels were quantified by an enzyme-linked immunosorbent assay. Joint cytokine and matrix metalloproteinases-3 levels were determined by a quantitative polymerase chain reaction. Splenic suppressors of cytokine signaling (SOCS) were determined by Western blot analysis as indices of systemic immunoresponse. IL-18Rα KO mice showed lower arthritis and histological scores in bone erosion and synovitis due to reductions in the infiltration of CD4+ T cells and F4/80+ cells and decreased serum IL-6, -18, TNF, and IFN-γ levels. The mRNA expression and protein levels of SOCS3 were significantly increased in the IL-18Rα KO mice. By an up-regulation of SOCS, pro-inflammatory cytokines were decreased through the IL-18/IL-18Rα signaling pathway. These results suggest that inhibitors of the IL-18/IL-18Rα signaling pathway could become new therapeutic agents for rheumatoid arthritis.
Genetic Associations with Aging Muscle: A Systematic Review
Authors: Pratt Jedd , Boreham Colin , Ennis Sean , Ryan Anthony W. , De Vito Giuseppe
Published: December 2019

The age-related decline in skeletal muscle mass, strength and function known as ‘sarcopenia’ is associated with multiple adverse health outcomes, including cardiovascular disease, stroke, functional disability and mortality. While skeletal muscle properties are known to be highly heritable, evidence regarding the specific genes underpinning this heritability is currently inconclusive. This review aimed to identify genetic variants known to be associated with muscle phenotypes relevant to sarcopenia. PubMed, Embase and Web of Science were systematically searched (from January 2004 to March 2019) using pre-defined search terms such as “aging”, “sarcopenia”, “skeletal muscle”, “muscle strength” and “genetic association”. Candidate gene association studies and genome wide association studies that examined the genetic association with muscle phenotypes in non-institutionalised adults aged ≥50 years were included. Fifty-four studies were included in the final analysis. Twenty-six genes and 88 DNA polymorphisms were analysed across the 54 studies. The ACTN3, ACE and VDR genes were the most frequently studied, although the IGF1/IGFBP3, TNFα, APOE, CNTF/R and UCP2/3 genes were also shown to be significantly associated with muscle phenotypes in two or more studies. Ten DNA polymorphisms (rs154410, rs2228570, rs1800169, rs3093059, rs1800629, rs1815739, rs1799752, rs7412, rs429358 and 192 bp allele) were significantly associated with muscle phenotypes in two or more studies. Through the identification of key gene variants, this review furthers the elucidation of genetic associations with muscle phenotypes associated with sarcopenia.
Perturbation of Nuclear Hormone Receptors by Endocrine Disrupting Chemicals: Mechanisms and Pathological Consequences of Exposure
Authors: Hall Julie M. , Greco Callie W.
Published: December 2019

Much of the early work on Nuclear Hormone Receptors (NHRs) focused on their essential roles as mediators of sex steroid hormone signaling in reproductive development and function, and thyroid hormone-dependent formation of the central nervous system. However, as NHRs display tissue-specific distributions and activities, it is not surprising that they are involved and vital in numerous aspects of human development and essential for homeostasis of all organ systems. Much attention has recently been focused on the role of NHRs in energy balance, metabolism, and lipid homeostasis. Dysregulation of NHR function has been implicated in numerous pathologies including cancers, metabolic obesity and syndrome, Type II diabetes mellitus, cardiovascular disease, hyperlipidemia, male and female infertility and other reproductive disorders. This review will discuss the dysregulation of NHR function by environmental endocrine disrupting chemicals (EDCs), and the associated pathological consequences of exposure in numerous tissues and organ systems, as revealed by experimental, clinical, and epidemiological studies.
Single-Cell Expression Variability Implies Cell Function
Authors: Osorio Daniel , Yu Xue , Zhong Yan , Li Guanxun , Serpedin Erchin , Huang Jianhua Z. , Cai James J.
Published: December 2019

As single-cell RNA sequencing (scRNA-seq) data becomes widely available, cell-to-cell variability in gene expression, or single-cell expression variability (scEV), has been increasingly appreciated. However, it remains unclear whether this variability is functionally important and, if so, what are its implications for multi-cellular organisms. Here, we analyzed multiple scRNA-seq data sets from lymphoblastoid cell lines (LCLs), lung airway epithelial cells (LAECs), and dermal fibroblasts (DFs) and, for each cell type, selected a group of homogenous cells with highly similar expression profiles. We estimated the scEV levels for genes after correcting the mean-variance dependency in that data and identified 465, 466, and 364 highly variable genes (HVGs) in LCLs, LAECs, and DFs, respectively. Functions of these HVGs were found to be enriched with those biological processes precisely relevant to the corresponding cell type’s function, from which the scRNA-seq data used to identify HVGs were generated—e.g., cytokine signaling pathways were enriched in HVGs identified in LCLs, collagen formation in LAECs, and keratinization in DFs. We repeated the same analysis with scRNA-seq data from induced pluripotent stem cells (iPSCs) and identified only 79 HVGs with no statistically significant enriched functions; the overall scEV in iPSCs was of negligible magnitude. Our results support the “variation is function” hypothesis, arguing that scEV is required for cell type-specific, higher-level system function. Thus, quantifying and characterizing scEV are of importance for our understating of normal and pathological cellular processes.
Identification of Astrocytoma Blood Serum Protein Profile
Authors: Vaitkiene Paulina , Urbanaviciute Ruta , Grigas Povilas , Steponaitis Giedrius , Tamasauskas Arimantas , Skiriutė Daina
Published: December 2019

High-grade astrocytomas are some of the most common and aggressive brain cancers, whose signs and symptoms are initially non-specific. Up to the present date, there are no diagnostic tools to observe the early onset of the disease. Here, we analyzed the combination of blood serum proteins, which may play key roles in the tumorigenesis and the progression of glial tumors. Fifty-nine astrocytoma patients and 43 control serums were analyzed using Custom Human Protein Antibody Arrays, including ten targets: ANGPT1, AREG, IGF1, IP10, MMP2, NCAM1, OPN, PAI1, TGFβ1, and TIMP1. The decision tree analysis indicates that serums ANGPT1, TIMP1, IP10, and TGFβ1 are promising combinations of targets for glioma diagnostic applications. The accuracy of the decision tree algorithm was 73.5% (75/102), which correctly classified 79.7% (47/59) astrocytomas and 65.1% (28/43) healthy controls. The analysis revealed that the relative value of osteopontin (OPN) protein level alone predicted the 12-month survival of glioblastoma (GBM) patients with the specificity of 84%, while the inclusion of the IP10 protein increased model predictability to 92.3%. In conclusion, the serum protein profiles of ANGPT1, TIMP1, IP10, and TGFβ1 were associated with the presence of astrocytoma independent of its malignancy grade, while OPN and IP10 were associated with GBM patient survival.
Mitochondrial Gene Expression and Beyond—Novel Aspects of Cellular Physiology
Authors: Kotrys Anna V. , Szczesny Roman J.
Published: December 2019

Mitochondria are peculiar organelles whose proper function depends on the crosstalk between two genomes, mitochondrial and nuclear. The human mitochondrial genome (mtDNA) encodes only 13 proteins; nevertheless, its proper expression is essential for cellular homeostasis, as mtDNA-encoded proteins are constituents of mitochondrial respiratory complexes. In addition, mtDNA expression results in the production of RNA molecules, which influence cell physiology once released from the mitochondria into the cytoplasm. As a result, dysfunctions of mtDNA expression may lead to pathologies in humans. Here, we review the mechanisms of mitochondrial gene expression with a focus on recent findings in the field. We summarize the complex turnover of mitochondrial transcripts and present an increasing body of evidence indicating new functions of mitochondrial transcripts. We discuss mitochondrial gene regulation in different cellular contexts, focusing on stress conditions. Finally, we highlight the importance of emerging aspects of mitochondrial gene regulation in human health and disease.
Brain-Derived Extracellular Vesicle microRNA Signatures Associated with In Utero and Postnatal Oxycodone Exposure
Authors: Shahjin Farah , Guda Rahul S. , Schaal Victoria L. , Odegaard Katherine , Clark Alexander , Gowen Austin , Xiao Peng , Lisco Steven J. , Pendyala Gurudutt , Yelamanchili Sowmya V.
Published: December 2019

Oxycodone (oxy) is a semi-synthetic opioid commonly used as a pain medication that is also a widely abused prescription drug. While very limited studies have examined the effect of in utero oxy (IUO) exposure on neurodevelopment, a significant gap in knowledge is the effect of IUO compared with postnatal oxy (PNO) exposure on synaptogenesis—a key process in the formation of synapses during brain development—in the exposed offspring. One relatively unexplored form of cell–cell communication associated with brain development in response to IUO and PNO exposure are extracellular vesicles (EVs). EVs are membrane-bound vesicles that serve as carriers of cargo, such as microRNAs (miRNAs). Using RNA-Seq analysis, we identified distinct brain-derived extracellular vesicle (BDEs) miRNA signatures associated with IUO and PNO exposure, including their gene targets, regulating key functional pathways associated with brain development to be more impacted in the IUO offspring. Further treatment of primary 14-day in vitro (DIV) neurons with IUO BDEs caused a significant reduction in spine density compared to treatment with BDEs from PNO and saline groups. In summary, our studies identified for the first time, key BDE miRNA signatures in IUO- and PNO-exposed offspring, which could impact their brain development as well as synaptic function.
Fibronectin in Cancer: Friend or Foe
Authors: Lin Tsung-Cheng , Yang Cheng-Han , Cheng Li-Hsin , Chang Wen-Tsan , Lin Yuh-Rong , Cheng Hung-Chi
Published: December 2019

The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is paradoxically related to a better prognosis. Here, we justify how FN impacts tumor transformation and subsequently metastatic progression. Next, we try to reconcile and rationalize the seemingly conflicting roles of FN in cancer and TMEs. Finally, we propose future perspectives for potential FN-based therapeutic strategies.
Oncostatin M, A Profibrogenic Mediator Overexpressed in Non-Alcoholic Fatty Liver Disease, Stimulates Migration of Hepatic Myofibroblasts
Authors: Foglia Beatrice , Sutti Salvatore , Pedicini Dario , Cannito Stefania , Bocca Claudia , Maggiora Marina , Bevacqua Maria Rosaria , Rosso Chiara , Bugianesi Elisabetta , Albano Emanuele , Novo Erica , Parola Maurizio
Published: December 2019

Background: Hepatic myofibroblasts (MFs) can originate from hepatic stellate cells, portal fibroblasts, or bone marrow-derived mesenchymal stem cells and can migrate towards the site of injury by aligning with nascent and established fibrotic septa in response to several mediators. Oncostatin M (OSM) is known to orchestrate hypoxia-modulated hepatic processes involving the hypoxia-inducible factor 1 (HIF-1). Methods. In vivo and in vitro experiments were performed to analyze the expression of OSM and OSM-receptor (OSMR) in three murine models of non-alcoholic-fatty liver disease (NAFLD) and -steatohepatitis (NASH) and in human NASH patients as well as the action of OSM on phenotypic responses of human MFs. Results: Hepatic OSM and OSMR levels were overexpressed in three murine NASH models and in NASH patients. OSM stimulates migration in human MFs by involving early intracellular ROS generation and activation of Ras/Erk, JNK1/2, PI3K/Akt as well as STAT1/STAT3 pathways and HIF-1α. OSM-dependent migration relies on a biphasic mechanism requiring early intracellular generation of reactive oxygen species (ROS) and late HIF1-dependent expression and release of VEGF. Conclusion: OSM is overexpressed in experimental and human progressive NAFLD and can act as a profibrogenic factor by directly stimulating migration of hepatic MFs.
Synergistic Effects of Nanomedicine Targeting TNFR2 and DNA Demethylation Inhibitor—An Opportunity for Cancer Treatment
Authors: Al-Hatamleh Mohammad A. I. , E.A.R. Engku Nur Syafirah , Boer Jennifer C. , Ferji Khalid , Six Jean-Luc , Chen Xin , Elkord Eyad , Plebanski Magdalena , Mohamud Rohimah
Published: December 2019

Tumor necrosis factor receptor 2 (TNFR2) is expressed on some tumor cells, such as myeloma, Hodgkin lymphoma, colon cancer and ovarian cancer, as well as immunosuppressive cells. There is increasingly evidence that TNFR2 expression in cancer microenvironment has significant implications in cancer progression, metastasis and immune evasion. Although nanomedicine has been extensively studied as a carrier of cancer immunotherapeutic agents, no study to date has investigated TNFR2-targeting nanomedicine in cancer treatment. From an epigenetic perspective, previous studies indicate that DNA demethylation might be responsible for high expressions of TNFR2 in cancer models. This perspective review discusses a novel therapeutic strategy based on nanomedicine that has the capacity to target TNFR2 along with inhibition of DNA demethylation. This approach may maximize the anti-cancer potential of nanomedicine-based immunotherapy and, consequently, markedly improve the outcomes of the management of patients with malignancy.
Conformational States of Exchange Protein Directly Activated by cAMP (EPAC1) Revealed by Ensemble Modeling and Integrative Structural Biology
Authors: White Mark Andrew , Tsalkova Tamara , Mei Fang C. , Cheng Xiaodong
Published: December 2019

Exchange proteins directly activated by cAMP (EPAC1 and EPAC2) are important allosteric regulators of cAMP-mediated signal transduction pathways. To understand the molecular mechanism of EPAC activation, we performed detailed Small-Angle X-ray Scattering (SAXS) analysis of EPAC1 in its apo (inactive), cAMP-bound, and effector (Rap1b)-bound states. Our study demonstrates that we can model the solution structures of EPAC1 in each state using ensemble analysis and homology models derived from the crystal structures of EPAC2. The N-terminal domain of EPAC1, which is not conserved between EPAC1 and EPAC2, appears folded and interacts specifically with another component of EPAC1 in each state. The apo-EPAC1 state is a dynamic mixture of a compact (Rg = 32.9 Å, 86%) and a more extended (Rg = 38.5 Å, 13%) conformation. The cAMP-bound form of EPAC1 in the absence of Rap1 forms a dimer in solution; but its molecular structure is still compatible with the active EPAC1 conformation of the ternary complex model with cAMP and Rap1. Herein, we show that SAXS can elucidate the conformational states of EPAC1 activation as it proceeds from the compact, inactive apo conformation through a previously unknown intermediate-state, to the extended cAMP-bound form, and then binds to its effector (Rap1b) in a ternary complex.
High Performance Multilayered Organosilicon/Silicon Oxynitride Water Barrier Structure Consecutively Deposited by Plasma-Enhanced Chemical Vapor Deposition at a Low-Temperature
Authors: Fu Ren-Da , Chang Che Kai , Chuang Ming-Yueh , Chen Tai-Hong , Lu Shao-Kai , Liu Day-Shan
Published: December 2019

In this study, pairs of the organosilicon/silicon oxynitride (SiOxNy) barrier structures with an ultralow water vapor transmittance rate (WVTR) were consecutively prepared by the plasma-enhanced chemical vapor deposition at a low temperature of 70 °C using the tetramethylsilane (TMS) monomer and the TMS-oxygen-ammonia gas mixture, respectively. The thickness of the SiOxNy film in the barrier structure was firstly designed by optimizing its effective permeability. The WVTR was further decreased by inserting an adequate thickness of the organosilicon layer as the stress residing in the barrier structure was released accordingly. By prolonging the diffusion pathway for water vapor permeation, three-paired organosilicon/SiOxNy multilayered barrier structure with a WVTR of about 10−5 g/m2/day was achievable for meeting the requirement of the thin film encapsulation on the organic light emitting diode.
Synergetic Approach for Superior Thermoelectric Performance in PbTe-PbSe-PbS Quaternary Alloys and Composites
Authors: Ginting Dianta , Lin Chan-Chieh , Rhyee Jong-Soo
Published: December 2019

Thermoelectric power generation is an energy conversion technology from heat to electric energy, which can be applied to waste heat power conversion. Among thermoelectric materials (TE), PbTe-PbSe-PbS quaternary alloys and composites are promising candidates for thermoelectric power generation applications in the mid-temperature operating range from 500 to ~850 K. Besides, the thermoelectric performance of quaternary alloys and composites is not fully optimized regarding its composition and synthesis process. In the quaternary system, PbTe-PbSe-PbS, it was found that PbS will form nanoprecipitation in the matrix of quaternary alloy for a small content of PbS (≤0.07), which reduces the lattice thermal conductivity. The power factor of PbTe-PbSe-PbS quaternary alloys can be significantly enhanced by using a band convergence in PbTe1−xSex. The band structure modifications, with the result of simultaneous PbS nanoprecipitation, give rise to a high Z T value of 2.3 at 800 K for (PbTe)0.95−x(PbSe)x(PbS)0.05. The chemical potential tuning by effective K-doping ( x = 0.02) and PbS substitution reveals a high power factor and low thermal conductivity, resulting in a comparatively high Z T value of 1.72 at 800 K. The combination of a high Seebeck coefficient and low thermal conductivity results in a very high Z T value of 1.52 at 700 K as n-type materials for low Cl-doped ( x = 0.0005) (PbTe0.93−xSe0.07Clx)0.93(PbS)0.07 composites. Therefore, this review presents the simultaneous emergence of effective chemical potential tuning, band convergence, and nanoprecipitation, giving rise to a significant enhancement of the thermoelectric performance of both p - and n -type PbTe-PbSe-PbS quaternary alloy and composite TE materials.
Computational Study of Flow and Heat Transfer Characteristics of EG-Si3N4 Nanofluid in Laminar Flow in a Pipe in Forced Convection Regime
Authors: Berberović Edin , Bikić Siniša
Published: December 2019

Laminar flow of ethylene glycol-based silicon nitride (EG-Si3N4) nanofluid in a smooth horizontal pipe subjected to forced heat convection with constant wall heat flux is computationally modeled and analyzed. Heat transfer is evaluated in terms of Nusselt number (Nu) and heat transfer coefficient for various volume fractions of Si3N4 nanoparticles in the base fluid and different laminar flow rates. The thermophysical properties of the EG-Si3N4 nanofluid are taken from a recently published experimental study. Computational modelling and simulation are performed using open-source software utilizing finite volume numerical methodology. The nanofluid exhibits non-Newtonian rheology and it is modelled as a homogeneous single-phase mixture, the properties of which are determined by the nanoparticle volume fraction. The existing features of the software to simulate single-phase flow are extended by implementing the energy transport coupled to the fluid flow and the interaction of the fluid flow with the surrounding pipe wall via the applied wall heat flux. In addition, the functional dependencies of the thermophysical properties of the nanofluid on the volume fraction of nanoparticles are implemented in the software, while the non-Newtonian rheological behavior of the nanofluid under consideration is also taken into account. The obtained results from the numerical simulations show very good predicting capabilities of the implemented computational model for the laminar flow coupled to the forced convection heat transfer. Moreover, the analysis of the computational results for the nanofluid reflects the increase of heat transfer of the EG-Si3N4 nanofluid in comparison to the EG for all the considered nanoparticle volume fractions and flow rates, indicating promising features of this nanofluid in heat transfer applications.
Intraspecific Diversity in the Cold Stress Response of Transposable Elements in the Diatom Leptocylindrus aporus
Authors: Pargana Aikaterini , Musacchia Francesco , Sanges Remo , Russo Monia Teresa , Ferrante Maria Immacolata , Bowler Chris , Zingone Adriana
Published: December 2019

Transposable elements (TEs), activated as a response to unfavorable conditions, have been proposed to contribute to the generation of genetic and phenotypic diversity in diatoms. Here we explore the transcriptome of three warm water strains of the diatom Leptocylindrus aporus, and the possible involvement of TEs in their response to changing temperature conditions. At low temperature (13 °C) several stress response proteins were overexpressed, confirming low temperature to be unfavorable for L. aporus, while TE-related transcripts of the LTR retrotransposon superfamily were the most enriched transcripts. Their expression levels, as well as most of the stress-related proteins, were found to vary significantly among strains, and even within the same strains analysed at different times. The lack of overexpression after many months of culturing suggests a possible role of physiological plasticity in response to growth under controlled laboratory conditions. While further investigation on the possible central role of TEs in the diatom stress response is warranted, the strain-specific responses and possible role of in-culture evolution draw attention to the interplay between the high intraspecific variability and the physiological plasticity of diatoms, which can both contribute to the adaptation of a species to a wide range of conditions in the marine environment.
Effects of Continuous Sugar Beet Cropping on Rhizospheric Microbial Communities
Authors: Huang Weijuan , Sun Donglei , Fu Jiantao , Zhao Huanhuan , Wang Ronghua , An Yuxing
Published: December 2019

The continuous cropping of sugar beet can result in soil degradation and a decrease in the sugar beet yield and quality. However, the role of continuous sugar beet (Beta vulgaris L. var. saccharifera) cropping in shaping the structure and function of the rhizosphere microbial community remains poorly investigated. In this study, we comparatively investigated the impact of different numbers of years of continuous sugar beet cropping on structural and functional changes in the microbial community of the rhizosphere using high-throughput sequencing and bioinformatics analysis. We collected rhizosphere soils from fields continuously cropped for one-year (T1), five-year (T5), and thirty-year (T30) periods, as well as one bulk soil (T0), in the Xinjiang Uygur Autonomous Region. The results demonstrated that continuous sugar beet cropping resulted in a significant decline in the community diversity of soil bacterial and fungal populations from T1 to T5. With continuous change in the structure of the microbial community, the Shannon diversity and observed species were increased in T30. With an abundance of pathogenic microbes, including Acidobacteria, Alternaria, and Fusarium, that were highly enriched in T30, soil-borne diseases could be accelerated, deduced by functional predictions based on 16S rRNA genes. Continuous sugar beet cropping also led to significant declines in beneficial bacteria, including Actinobacteria, Pseudomonas spp., and Bacillus spp. In addition, we profiled and analyzed predictive metabolic characteristics (metabolism and detoxification). The abundance of phenolic acid decarboxylase involved in the phenolic acid degradation pathway was significantly lower in groups T5 and T30 than that in T0 and T1, which could result in the phenolic compounds becoming excessive in long-term continuous cropping soil. Our results provide a deeper understanding of the rhizosphere soil microbial community’s response to continuous sugar beet cropping, which is important in evaluating the sustainability of this agricultural practice.
Colony-Forming Unit Spreadplate Assay versus Liquid Culture Enrichment-Polymerase Chain Reaction Assay for the Detection of Bacillus Endospores in Soils
Authors: Griffin Dale W. , Lisle John T. , Feldhake David , Silvestri Erin E.
Published: December 2019

A liquid culture enrichment-polymerase chain reaction (E-PCR) assay was investigated as a potential tool to overcome inhibition by chemical component, debris, and background biological impurities in soil that were affecting detection assay performance for soil samples containing Bacillus atrophaeus subsp. globigii (a surrogate for B. anthracis). To evaluate this assay, 9 g of matched sets of three different soil types (loamy sand [sand], sandy loam [loam] and clay) was spiked with 0, ~4.5, 45, 225, 675 and 1350 endospores. One matched set was evaluated using a previously published endospore concentration and colony-forming unit spreadplate (CFU-S) assay and the other matched set was evaluated using an E-PCR assay to investigate differences in limits of detection between the two assays. Data illustrated that detection using the CFU-S assay at the 45-endospore spike level started to become sporadic whereas the E-PCR assay produced repeatable detection at the ~4.5-endospore spike concentration. The E-PCR produced an ~2-log increase in sensitivity and required slightly less time to complete than the CFU-S assay. This study also investigated differences in recovery among pure and blended sand and clay soils and found potential activation of B. anthracis in predominately clay-based soils.
Bone Marrow-Derived Mesenchymal Stromal Cells: A Novel Target to Optimize Hematopoietic Stem Cell Transplantation Protocols in Hematological Malignancies and Rare Genetic Disorders
Authors: Crippa Stefania , Santi Ludovica , Bosotti Roberto , Porro Giulia , Bernardo Maria Ester
Published: December 2019

Mesenchymal stromal cells (MSCs) are crucial elements in the bone marrow (BM) niche where they provide physical support and secrete soluble factors to control and maintain hematopoietic stem progenitor cells (HSPCs). Given their role in the BM niche and HSPC support, MSCs have been employed in the clinical setting to expand ex-vivo HSPCs, as well as to facilitate HSPC engraftment in vivo. Specific alterations in the mesenchymal compartment have been described in hematological malignancies, as well as in rare genetic disorders, diseases that are amenable to allogeneic hematopoietic stem cell transplantation (HSCT), and ex-vivo HSPC-gene therapy (HSC-GT). Dissecting the in vivo function of human MSCs and studying their biological and functional properties in these diseases is a critical requirement to optimize transplantation outcomes. In this review, the role of MSCs in the orchestration of the BM niche will be revised, and alterations in the mesenchymal compartment in specific disorders will be discussed, focusing on the need to correct and restore a proper microenvironment to ameliorate transplantation procedures, and more in general disease outcomes.
Machine Learning of Infant Spontaneous Movements for the Early Prediction of Cerebral Palsy: A Multi-Site Cohort Study
Authors: Ihlen Espen A. F. , Støen Ragnhild , Boswell Lynn , de Regnier Raye-Ann , Fjørtoft Toril , Gaebler-Spira Deborah , Labori Cathrine , Loennecken Marianne C. , Msall Michael E. , Möinichen Unn I. , Peyton Colleen , Schreiber Michael D. , Silberg Inger E. , Songstad Nils T. , Vågen Randi T. , Øberg Gunn K. , Adde Lars
Published: December 2019

Background: Early identification of cerebral palsy (CP) during infancy will provide opportunities for early therapies and treatments. The aim of the present study was to present a novel machine-learning model, the Computer-based Infant Movement Assessment (CIMA) model, for clinically feasible early CP prediction based on infant video recordings. Methods: The CIMA model was designed to assess the proportion (%) of CP risk-related movements using a time–frequency decomposition of the movement trajectories of the infant’s body parts. The CIMA model was developed and tested on video recordings from a cohort of 377 high-risk infants at 9–15 weeks corrected age to predict CP status and motor function (ambulatory vs. non-ambulatory) at mean 3.7 years age. The performance of the model was compared with results of the general movement assessment (GMA) and neonatal imaging. Results: The CIMA model had sensitivity (92.7%) and specificity (81.6%), which was comparable to observational GMA or neonatal cerebral imaging for the prediction of CP. Infants later found to have non-ambulatory CP had significantly more CP risk-related movements (median: 92.8%, p = 0.02) compared with those with ambulatory CP (median: 72.7%). Conclusion: The CIMA model may be a clinically feasible alternative to observational GMA.
Identification of the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire—IUGA Revised (PISQ-IR) Cutoff Scores for Impaired Sexual Function in Women with Pelvic Floor Disorders
Authors: Grzybowska Magdalena Emilia , Futyma Konrad , Wydra Dariusz
Published: December 2019

The aim of this cross-sectional study was to determine the cutoff scores for sexual dysfunction in disease-specific Pelvic Organ Prolapse/Incontinence Sexual Questionnaire—IUGA Revised (PISQ-IR) for women with pelvic floor disorders (PFD). Medical history and urogynecological data of 521 women with PFD were collected. The subjects provided information about their sexual activity and completed Female Sexual Function Index (FSFI) and PISQ-IR questionnaires. Sexually active (SA) women were further analyzed and categorized using their FSFI scores: <26.55—sexual dysfunction, >26.55—no sexual dysfunction. Receiver operating characteristics (ROC) curve tested how well PISQ-IR allowed to discriminate between patients with and without sexual disorders. Area under curve (AUC) was calculated to measure the PISQ-IR Summary Score efficiency in the prediction. The cutoff values which minimalize (1-specifity) and maximize sensitivity were selected. In the analyzed cohort, 250 (48%) women were SA and a total of 226 SA were recruited for the study: 143 (63.3%) with <26.55 FSFI and 83 (36.7%) with >26.55 FSFI (response rate: 90.4%). Using ROC curve analysis, PISQ-IR Summary Score of 2.68 was determined to be the optimal cutoff for distinguishing between dysfunctional and nondysfunctional women (AUC = 0.85), allowing to diagnose sexual dysfunction in SA women with PFD, with 90% sensitivity and 71% specificity.
Early Recovery of Left Ventricular Function After Revascularization in Acute Coronary Syndrome
Authors: Shenouda Rafik , Bytyçi Ibadete , Sobhy Mohamed , Henein Michael Y.
Published: December 2019

The aim of this study was to assess the accuracy of echocardiographic techniques in detecting the early recovery of left ventricular (LV) function after revascularization in acute coronary syndrome (ACS). In 80 consecutive patients with ACS (age 55.7 ± 9.4 years, 77% male, 15% with CCS Angina III), an echocardiographic examination of left ventricle regional wall motion abnormalities (LV RWMA), peak systolic strain rate (PSSR), peak systolic strain (PSS) and end systolic strain (ESS) was performed before and after percutaneous intervention (PCI). Of the 80 patients, one vessel stenosis (>70%) was present in 53 (66%), two vessel disease in 12 (15%) and multivessel disease in 15 patients (19%). In total, 51% of patients had hypertension, 40% diabetes and 23% dyslipidemia. After PCI, regional PSS, ESS and PSSR of their segments subtended by the culprit vessel improved; left anterior descending-LAD, circumflex-LCx and right coronary-RCA (p<0.05 for all) as well as global S and SR (p < 0.05 for all). In univariate analysis, hypertension (HTN) (β = −0.294 (−0.313–0.047), p = 0.009, smoking β = −0.244 (−0.289–0.015) =0.03, WMA β = −0.317 (−0.284–0.014), p = 0.004 and the number of diseased vessels β = −0.256 (−0.188– 0.054) p=0.03 were predictors of delta global SR. In multivariate analysis, only HTN β = 0.263 (0.005–3.159) and the number of diseased vessels β =0.263 (0.005 - 3.159), p=0.04) predicted delta global SR. In ACS, the echocardiographic regional myocardial deformation is accurate in detecting early recovery of LV myocardial function after culprit lesion revascularization. Also, the findings of this study support the current practice regarding the crucial importance of proximal epicardial vessel PCI treatment on LV function compared to more distal lesions.
Nutritional Management and Outcomes in Malnourished Medical Inpatients in 2020: The Evidence Is Growing!
Authors: Schuetz Philipp , Stanga Zeno
Published: December 2019

Access to adequate food is a fundamental human right [...]
Association between Gait Deviation Index and Physical Function in Children with Bilateral Spastic Cerebral Palsy: A Cross-Sectional Study
Authors: Ito Tadashi , Noritake Koji , Sugiura Hiroshi , Kamiya Yasunari , Tomita Hidehito , Ito Yuji , Sugiura Hideshi , Ochi Nobuhiko , Yoshihashi Yuji
Published: December 2019

This study examined the association between Gait Deviation Index (GDI) and the five-times-sit-to-stand test (FTSST) or gait speed results, which represent mobility and muscle strength of the lower extremities in ambulatory children with Gross Motor Function Classification System (GMFCS) level I and II spastic cerebral palsy. In this cross-sectional, observational study, three-dimensional gait analysis data were obtained during gait trials to evaluate the GDI in 35 children (age 5–16 years) with spastic palsy. Motor function was evaluated using FTSST and gait speed. Gross motor function was evaluated using GMFCS. Children with GMFCS level II spastic cerebral palsy demonstrated lower GDI (p < 0.001) and poorer FTSST (p = 0.031) than those with GMFCS level I spastic cerebral palsy. Correlation analysis showed that FTSST results were significantly correlated with GDI (r = −0.624; p < 0.001). Motor function may be important for the maintenance of gait quality in patients with GMFCS level I and II spastic cerebral palsy and should not be ignored. In conclusion, reduction in gait impairment may affect the values of FTSST and GDI in patients with spastic cerebral palsy who can ambulate without an assistive device.
Incommensurately Modulated Crystal Structure and Photoluminescence Properties of Eu2O3- and P2O5-Doped Ca2SiO4 Phosphor
Authors: Nakano Hiromi , Ando Shota , Kamimoto Konatsu , Hiramatsu Yuya , Michiue Yuichi , Hirosaki Naoto , Fukuda Koichiro
Published: December 2019

We prepared four types of Eu2O3- and P2O5-doped Ca2SiO4 phosphors with different phase compositions but identical chemical composition, the chemical formula of which was (Ca1.950Eu3+0.013☐0.037)(Si0.940P0.060)O4 (☐ denotes vacancies in Ca sites). One of the phosphors was composed exclusively of the incommensurate (IC) phase with superspace group Pnma(0β0)00s and basic unit-cell dimensions of a = 0.68004(2) nm, b = 0.54481(2) nm, and c = 0.93956(3) nm (Z = 4). The crystal structure was made up of four types of β-Ca2SiO4-related layers with an interlayer. The incommensurate modulation with wavelength of 4.110 × b was induced by the long-range stacking order of these layers. When increasing the relative amount of the IC-phase with respect to the coexisting β-phase, the red light emission intensity, under excitation at 394 nm, steadily decreased to reach the minimum, at which the specimen was composed exclusively of the IC-phase. The coordination environments of Eu3+ ion in the crystal structures of β- and IC-phases might be closely related to the photoluminescence intensities of the phosphors.
Characterization of Nme5-Like Gene/Protein from the Red Alga Chondrus Crispus
Authors: Perina Dragutin , Korolija Marina , Mikoč Andreja , Halasz Mirna , Herak Bosnar Maja , Ćetković Helena
Published: December 2019

The Nme gene/protein family of nucleoside diphosphate kinases (NDPK) was originally named after its member Nm23-H1/Nme1, the first identified metastasis suppressor. Human Nme proteins are divided in two groups. They all possess nucleoside diphosphate kinase domain (NDK). Group I (Nme1-Nme4) display a single type NDK domain, whereas Group II (Nme5-Nme9) display a single or several different NDK domains, associated or not associated with extra-domains. Data strongly suggest that, unlike Group I, none of the members of Group II display measurable NDPK activity, although some of them autophosphorylate. The multimeric form is required for the NDPK activity. Group I proteins are known to multimerize, while there are no data on the multimerization of Group II proteins. The Group II ancestral type protein was shown to be conserved in several species from three eukaryotic supergroups. Here, we analysed the Nme protein from an early branching eukaryotic lineage, the red alga Chondrus crispus. We show that the ancestral type protein, unlike its human homologue, was fully functional multimeric NDPK with high affinity to various types of DNA and dispersed localization throughout the eukaryotic cell. Its overexpression inhibits both cell proliferation and the anchorage-independent growth of cells in soft agar but fails to deregulate cell apoptosis. We conclude that the ancestral gene has changed during eukaryotic evolution, possibly in correlation with the protein function.
Glutathione Injection Alleviates the Fluctuation of Metabolic Response under Thermal Stress in Olive Flounder, Paralichthys olivaceus
Authors: Kim Seonghye , Kim Ahran , Ma Seohee , Lee Wonho , Lee Sujin , Yoon Dahye , Kim Do-Hyung , Kim Suhkmann
Published: December 2019

Continuous increases in water temperature disturb homeostasis and increase oxidative stress in fish. Glutathione (GSH) is an intracellular antioxidant that helps to relieve stress in animals. In this study, we observed the effect of GSH on olive flounder exposed to high temperature using serum parameters and NMR-based metabolomics. Based on the results from the first experiment, 20 mg of GSH was chosen as an effective dose with lower infection rates and mortality. Then, fish were divided into Control, Temp (PS injection), and GSH (glutathione injection) groups, and fish in Temp and GSH groups were exposed to temperature fluctuations (20 °C→24 °C→27 °C). In OPLS-DA score plots, Temp group was clearly distinguished from the other groups in the kidney. In the liver, the metabolic patterns of GSH group were close to the Temp group on day 4 and became similar to Control group from day 7. Serum parameters did not change significantly, but the deviation in Temp group was greater than that in GSH group. Metabolite levels that were significantly altered included GSH, lactate, O-phosphocholine, and betaine in the kidney and taurine, glucose, and several amino acids in the liver, which were related to antioxidant activity and energy system. Therefore, GSH supplements could relieve thermal stress influencing metabolic mechanisms in fish.
Proton NMR Enables the Absolute Quantification of Aqueous Metabolites and Lipid Classes in Unique Mouse Liver Samples
Authors: Amiel Aurélien , Tremblay-Franco Marie , Gautier Roselyne , Ducheix Simon , Montagner Alexandra , Polizzi Arnaud , Debrauwer Laurent , Guillou Hervé , Bertrand-Michel Justine , Canlet Cécile
Published: December 2019

Hepatic metabolites provide valuable information on the physiological state of an organism, and thus, they are monitored in many clinical situations. Typically, monitoring requires several analyses for each class of targeted metabolite, which is time consuming. The present study aimed to evaluate a proton nuclear magnetic resonance (1H-NMR) method for obtaining quantitative measurements of aqueous and lipidic metabolites. We optimized the extraction protocol, the standard samples, and the organic solvents for the absolute quantification of lipid species. To validate the method, we analyzed metabolic profiles in livers of mice fed three different diets. We compared our results with values obtained with conventional methods and found strong correlations. The 1H-NMR protocol enabled the absolute quantification of 29 aqueous metabolites and eight lipid classes. Results showed that mice fed a diet enriched in saturated fatty acids had higher levels of triglycerides, cholesterol ester, monounsaturated fatty acids, lactate, 3-hydroxy-butyrate, and alanine and lower levels of glucose, compared to mice fed a control diet. In conclusion, proton NMR provided a rapid overview of the main lipid classes (triglycerides, cholesterol, phospholipids, fatty acids) and the most abundant aqueous metabolites in liver.
Biotransformation of Monocyclic Phenolic Compounds by Bacillus licheniformis TAB7
Authors: Mpofu Enock , Chakraborty Joydeep , Suzuki-Minakuchi Chiho , Okada Kazunori , Kimura Toshiaki , Nojiri Hideaki
Published: December 2019

Bacillus licheniformis strain TAB7 is a bacterium used as a commercial deodorizing agent for compost in Japan. In this work, its ability to biotransform the following monocyclic phenolic compounds was assessed: ferulate, vanillate, p-coumarate, caffeate, protocatechuate, syringate, vanillin, and cinnamate (a precursor for some phenolic compounds). These compounds are abundant in composting material and are reported to have allelopathic properties. They come from sources such as plant material decomposition or agro-industrial waste. Biotransformation assays were carried out in LB supplemented with 0.2 mg/mL of an individual phenolic compound and incubated for up to 15 days followed by extraction and HPLC analysis. The results showed that TAB7 could biotransform ferulate, caffeate, p-coumarate, vanillate, protocatechuate, and vanillin. It, however, had a poor ability to transform cinnamate and syringate. LC-MS/MS analysis showed that ferulate was transformed into 4-vinylguaiacol as the final product, while caffeate was transformed into 4-ethylcatechol. TAB7 genome analysis suggested that, while TAB7 may not mineralize phenolic compounds, it harbored genes possibly encoding phenolic acid decarboxylase, vanillate decarboxylase, and some protocatechuate degradation pathway enzymes, which are involved in the catabolism of phenolic compounds known to have negative allelopathy on some plants. The results thus suggested that TAB7 can reduce such phenolic compounds in compost.
Aptamers Chemistry: Chemical Modifications and Conjugation Strategies
Authors: Odeh Fadwa , Nsairat Hamdi , Alshaer Walhan , Ismail Mohammad A. , Esawi Ezaldeen , Qaqish Baraa , Bawab Abeer Al , Ismail Said I.
Published: December 2019

Soon after they were first described in 1990, aptamers were largely recognized as a new class of biological ligands that can rival antibodies in various analytical, diagnostic, and therapeutic applications. Aptamers are short single-stranded RNA or DNA oligonucleotides capable of folding into complex 3D structures, enabling them to bind to a large variety of targets ranging from small ions to an entire organism. Their high binding specificity and affinity make them comparable to antibodies, but they are superior regarding a longer shelf life, simple production and chemical modification, in addition to low toxicity and immunogenicity. In the past three decades, aptamers have been used in a plethora of therapeutics and drug delivery systems that involve innovative delivery mechanisms and carrying various types of drug cargos. However, the successful translation of aptamer research from bench to bedside has been challenged by several limitations that slow down the realization of promising aptamer applications as therapeutics at the clinical level. The main limitations include the susceptibility to degradation by nucleases, fast renal clearance, low thermal stability, and the limited functional group diversity. The solution to overcome such limitations lies in the chemistry of aptamers. The current review will focus on the recent arts of aptamer chemistry that have been evolved to refine the pharmacological properties of aptamers. Moreover, this review will analyze the advantages and disadvantages of such chemical modifications and how they impact the pharmacological properties of aptamers. Finally, this review will summarize the conjugation strategies of aptamers to nanocarriers for developing targeted drug delivery systems.
P-MAPA and Interleukin-12 Reduce Cell Migration/Invasion and Attenuate the Toll-Like Receptor-Mediated Inflammatory Response in Ovarian Cancer SKOV-3 Cells: A Preliminary Study
Authors: Lupi Luiz Antonio , Delella Flávia Karina , Cucielo Maira Smaniotto , Romagnoli Graziela Gorete , Kaneno Ramon , Nunes Iseu da Silva , Domeniconi Raquel Fantin , Martinez Marcelo , Martinez Francisco Eduardo , Fávaro Wagner José , Chuffa Luiz Gustavo de Almeida
Published: December 2019

Immunotherapies have emerged as promising complementary treatments for ovarian cancer (OC), but its effective and direct role on OC cells is unclear. This study examined the combinatory effects of the protein aggregate magnesium–ammonium phospholinoleate–palmitoleate anhydride, known as P-MAPA, and the human recombinant interleukin-12 (hrIL-12) on cell migration/invasion, apoptosis, toll-like receptor (TLR)-mediated inflammation, and cytokine/chemokine profile in human OC cell line SKOV-3. P-MAPA and IL-12 showed cancer cell toxicity under low doses after 48 h. Although apoptosis/necrosis and the cell cycle were unchanged by the treatments, P-MAPA enhanced the sensitivity to paclitaxel (PTX) and P-MAPA associated with IL-12 significantly reduced the migratory potential and invasion capacity of SKOV-3 cells. P-MAPA therapy reduced TLR2 immunostaining and the myeloid differentiation factor 88 (MyD88), but not the TLR4 levels. Moreover, the combination of P-MAPA with IL-12 attenuated the levels of MyD88, interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-kB p65). The IL-12 levels were increased and P-MAPA stimulated the secretion of cytokines IL-3, IL-9, IL-10, and chemokines MDC/CCL22 and, regulated on activation, normal T cells expressed and secreted (RANTES)/CCL5. Conversely, combination therapy reduced the levels of IL-3, IL-9, IL-10, MDC/CCL22, and RANTES/CCL5. Collectively, P-MAPA and IL-12 reduce cell dynamics and effectively target the TLR-related downstream molecules, eliciting a protective effect against chemoresistance. P-MAPA also stimulates the secretion of anti-inflammatory molecules, possibly having an immune response in the OC microenvironment.