bluuebunny/crossref_metadata_2025 huggingface dataset:
Achieving the Sustainable Development Goals: A Mixed Methods Study of Health-Related Water, Sanitation, and Hygiene (WASH) for Indigenous Shawi in the Peruvian Amazon
Authors: Torres-Slimming Paola A. , Wright Carlee , Carcamo Cesar P. , Garcia Patricia J. , Research Team IHACC , Harper Sherilee L.
Published: July 2019

Sustainable Development Goal 6 (SDG-6) addresses poor water quality, inadequate sanitation, and improper hygiene, all of which negatively impact health and disproportionately impact Indigenous Peoples’ health. Understanding and responding to local contexts is critical to effectively improve water, sanitation, and hygiene (WASH); however, in-depth understanding of local knowledge, practices, and perceptions are often overlooked. As such, this study described the knowledge, practices, and perceptions of WASH held by residents of two Indigenous Shawi communities in the Peruvian Amazon. Quantitative data were collected via a cross-sectional survey and analyzed using descriptive statistics. Qualitative data were collected via interviews, PhotoVoice, focus group discussions, and participatory transect walks, and analyzed using a constant comparative approach to thematic analysis. Emergent themes included characterizing water sources, collection methods, and consumption patterns; knowledge, perceptions, and practices related to WASH; and knowledge and perceptions of health issues related to WASH. This study provides insight into the ongoing challenges related to WASH in Indigenous communities in the Peruvian Amazon and highlights the need to prioritize interventions that will advance WASH-related SDGs.
Assessment of Heavy Metal Pollution and Potential Ecological Risk in Sewage Sludge from Municipal Wastewater Treatment Plant Located in the Most Industrialized Region in Poland—Case Study
Authors: Tytła Malwina
Published: July 2019

This study aimed to assess the pollution and potential ecological risk of seven heavy metals (Cd, Cr, Cu, Hg, Ni, Pb, and Zn) in the sewage sludge collected from a wastewater treatment plant (WWTP), located in the most industrialized region of Poland (Silesian Voivodeship). The concentrations of heavy metals were determined using inductively coupled plasma optical spectrometry (ICP-OES) and cold vapor atomic absorption spectrometry (CVAAS). The chemical forms (chemical speciation) of heavy metals were determined using the three-step chemical sequential extraction procedure, developed by the Community Bureau of Reference (BCR). To assess the pollution level and potential ecological risk, the following indices were used: Geoaccumulation Index (Igeo), Potential Ecological Risk Factor (ER), Individual Contamination Factor (ICF), modified Risk Assessment Code (RACm), and Ecological Risk Factor (ERF)—the author’s index. Sludge samples were collected at successive stages of processing. The results revealed that the activated sludge process and sludge thickening have a significant impact on heavy metal distribution, while anaerobic digestion and dehydration decrease their mobility. The most dominant metals in the sludge samples were Zn and Cu. However, the content of heavy metals in sewage sludge did not exceed the permissible standards for agricultural purposes. The concentrations of heavy metals bound to the immobile fractions exhibited higher concentrations, compared to those bound to mobile fractions (except Zn). The values of the total indices indicated that sludge samples were moderately to highly contaminated with Zn, Hg, Cd, Cu, and Pb, of which only Hg, Cd, and Cu posed a potential ecological risk, while according to the speciation indices, sludge samples were moderately to very highly polluted with Zn, Cu, Cd, Cr, and Ni, of which Zn, Ni, and Cd were environmentally hazardous. The obtained results proved that assessment of the pollution level and potential ecological risk of heavy metals in sewage sludge requires knowledge on both their total concentrations and their chemical forms. Such an approach will help prevent secondary pollution of soils with heavy metals, which may influence the reduction of health risks associated with the consumption of plants characterized by a high metal content.
Narrative Review: The (Mental) Health Consequences of the Northern Iraq Offensive of ISIS in 2014 for Female Yezidis
Authors: Jäger Pia , Rammelt Claudia , Ott Notburga , Brand Angela
Published: July 2019

The Yezidis who represent a religious minority living in Northern Iraq were particularly affected by the persecution by ISIS (Islamic state of Iraq and Syria, syn.: ISIL—Islamic state of Iraq and the Levant) that gained power after 2013. This paper gives an overview of the events and the mental health consequences on the Yezidi community as well as associated influences on affected female Yezidis. Based on a systematic literature search, the aspects of “Persecution by ISIS and actual situation of the Yezidi community”, “Gender-specific aspects of the persecution and its consequences”, “Mental health of the affected women”, and “Cultural–historical and religious context” are worked out. Research indicates a high burden of health strain and mental health problems in the surviving Yezidi women, especially post-traumatic stress disorders (PTSD) and depression. Concerning transgenerational trauma, the recent genocide has revived past experiences in the history of the community. Like the narrow cultural and religious rules of the community, this can be both a resource and a burden. The actual extent of the attacks is neither predictable for the affected individuals nor for the community, consequences could also be passed onto descendants. Long-term care and support of the affected persons, their descendants, and the Yezidi community seems indispensable.
State-Level Affordability of Factory-Made Cigarettes among Current US Smokers: Findings from the ITC US Survey, 2003–2015
Authors: Driezen Pete , Nargis Nigar , Thompson Mary E. , Cummings K. Michael , Fong Geoffrey T. , Chaloupka Frank J. , Shang Ce , Cheng Kai-Wen
Published: July 2019

Cigarette affordability measures the price smokers pay for cigarettes in relation to their incomes. Affordability can be measured using the relative income price of cigarettes (RIP), or the price smokers pay to purchase 100 packs of 20 cigarettes divided by their per capita household income. Using longitudinal data from 7046 smokers participating in the International Tobacco Control (ITC) US Survey, the purpose of this study was to test whether affordability significantly changed following the US federal tax increase implemented on 1 April 2009. This study also estimated temporal trends in affordability from 2003–2015 at state and national levels using small area estimation methods and segmented linear mixed effects regression models. RIP increased slightly during 2003–2008. This was followed by a 30% increase during 2008–2010, indicating cigarettes were less affordable after the federal tax increase. RIP continued to increase during 2010–2013 but decreased during 2013–2015, suggesting cigarettes have recently become more affordable for US smokers. State-level trends in RIP were consistent with overall national trends. Controlling for other factors, a $1 increase in the state excise tax was significantly associated with a 9% increase in RIP, indicating state taxes reduced affordability. Tax-induced price increases must keep pace with underlying economic conditions to ensure cigarettes do not become more affordable over time.
The New Path to Improve Construction Safety Performance in China: An Evolutionary Game Theoretic Approach
Authors: Pi Zongjie , Gao Xin , Chen Linyan , Liu Jinghua
Published: July 2019

Evidence shows that there are many work-related accidents and injuries happening in construction projects and governments have taken a series of administrative measures to reduce casualties in recent years. However, traditional approaches have reached a bottleneck due to ignoring market forces, and thus new measures should be conducted. This study develops a perspective of safety performance (SP) for construction projects in China and puts forward a conception of the safety information system by using several brainstorming sessions to strengthen the safety supervision of participants in the construction industry. This system provides rating information to the public, and bad performance contractors enter into a blacklist which will influence their economic activities. Considering the limited rationality of government and various contractors, this paper builds a reasonable evolutionary game model to verify the feasibility of the safety information system. The analysis results show that there is not a single set of evolutionarily stable strategies (ESSs), as different situations may lead to different ESSs. The efficiency of applying the safety information system (the blacklist) in the construction industry can be proved by reducing the government’s safety supervision cost and by enhancing construction safety at the same time.
A Case Study of a Natural Experiment Bridging the ‘Research into Policy’ and ‘Evidence-Based Policy’ Gap for Active-Living Science
Authors: Hooper Paula , Foster Sarah , Giles-Corti Billie
Published: July 2019

The translation of research into tangible health benefits via changes to urban planning policy and practice is a key intended outcome of academic active-living research endeavours. Conversely, policy-makers and planners identify the need for policy-specific evidence to ensure policy decisions and practices are informed and validated by rigorously established evidence. In practice, however, these two aspirations rarely meet and a research-translation gap remains. The RESIDE project is a unique longitudinal natural experiment designed to evaluate the health impacts of the ‘Liveable Neighbourhoods’ planning policy, which was introduced by the Western Australian Government to create more walkable suburbs. This commentary provides an overview and discussion of the policy-specific study methodologies undertaken to quantitatively assess the implementation of the policy and assess its active living and health impacts. It outlines the key research-translation successes and impact of the findings on the Liveable Neighbourhoods policy and discusses lessons learnt from the RESIDE project to inform future natural experiments of policy evaluation.
Socio-Demographic Variation, Perceived Oral Impairment and Oral Impact on Daily Performance among Children in Saudi Arabia
Authors: Kassim Saba , Bakeer Hala , Alghazy Shahad , Almaghraby Yara , Sabbah Wael , Alsharif Alla
Published: July 2019

Background: This study aimed to describe the oral impact (estimate, severity, frequency) on daily performance (e.g., eating, speaking) and identify the potential perceived oral impairment(s) and socio-behavioral factors associated with oral impact, namely presence or absence of oral impact, among children aged 9–12 years old in Al-Madinah Al-Munawwarah, Saudi Arabia. Methods: A cross-sectional convenience sample of 186 children aged 9–12 years old was recruited. Sociodemographic characteristics, oral health-related behaviors, and perceived oral impairments (e.g., caries, toothache) were obtained from participants. The validated Arabic Child Oral Impact on Daily Performance (C-OIDP) inventory was used to assess oral impacts. Sample descriptive statistics and multivariable logistic regressions modeling the association between C-OIDP and explanatory variables were performed. Results: The mean (±SD) age of the children was 10.29 ± 1.24 years, 66.4% were from public schools, and 52% were females. At least one C-OIDP was reported by 78% of the participants. The mean C-OIDP score was 2.27 ± 1.99. Toothache was reported as a perceived impairment for almost all oral impacts and was the strongest predictor of C-OIDP. Low father income was negatively associated with C-OIDP (odds ratio (OR) = 0.24, 95% confidence interval (CI) = 0.10–0.62). Females had significantly higher odds of reporting C-OIDP than males. Conclusions: In this convenience sample, a high percentage of children aged 9–12 years old reported C-OIDP, which was linked to oral impairment and socio-demographic factors. Further studies, however, are required to explore the clinical, behavioral, and sociodemographic factors in relationship to C-OIDP among Saudi children in a representative sample.
Interventions to Promote Early Discharge and Avoid Inappropriate Hospital (Re)Admission: A Systematic Review
Authors: Coffey Alice , Leahy-Warren Patricia , Savage Eileen , Hegarty Josephine , Cornally Nicola , Day Mary Rose , Sahm Laura , O’Connor Kieran , O’Doherty Jane , Liew Aaron , Sezgin Duygu , O’Caoimh Rónán
Published: July 2019

Increasing pressure on limited healthcare resources has necessitated the development of measures promoting early discharge and avoiding inappropriate hospital (re)admission. This systematic review examines the evidence for interventions in acute hospitals including (i) hospital-patient discharge to home, community services or other settings, (ii) hospital discharge to another care setting, and (iii) reduction or prevention of inappropriate hospital (re)admissions. Academic electronic databases were searched from 2005 to 2018. In total, ninety-four eligible papers were included. Interventions were categorized into: (1) pre-discharge exclusively delivered in the acute care hospital, (2) pre- and post-discharge delivered by acute care hospital, (3) post-discharge delivered at home and (4) delivered only in a post-acute facility. Mixed results were found regarding the effectiveness of many types of interventions. Interventions exclusively delivered in the acute hospital pre-discharge and those involving education were most common but their effectiveness was limited in avoiding (re)admission. Successful pre- and post-discharge interventions focused on multidisciplinary approaches. Post-discharge interventions exclusively delivered at home reduced hospital stay and contributed to patient satisfaction. Existing systematic reviews on tele-health and long-term care interventions suggest insufficient evidence for admission avoidance. The most effective interventions to avoid inappropriate re-admission to hospital and promote early discharge included integrated systems between hospital and the community care, multidisciplinary service provision, individualization of services, discharge planning initiated in hospital and specialist follow-up.
Determination of the Role and Active Sites of PKC-Delta-Like from Lamprey in Innate Immunity
Authors: Xu Yang , Zhao Huan , Tian Yang , Ren Kaixia , Zheng Nan , Li Qingwei
Published: July 2019

Protein kinase C-δ (PKC-δ) is an important protein in the immune system of higher vertebrates. Lampreys, as the most primitive vertebrates, have a uniquevariable lymphocyte receptor (VLR) immune system. PKC-δ-like is a crucial functional gene in lampreys and is highly expressed in their immune organs. In this study, lampreys were stimulated with different immunogens, and lipopolysaccharide (LPS) was found to increase the expression of PKC-δ-like. Overexpression of PKC-δ-like could also effectively activate the innate immune response. We further demonstrated that PKC-δ-like-CF, a catalytic fragment of PKC-δ-like, is responsible for activating the innate immune response, and Thr-211, which is Thr-419 of PKC-δ-like, was confirmed to be the key site affecting PKC-δ-like-CF activity. These results indicated that PKC-δ-like from lamprey may have an important role in the innate immune response.
High Functioning Autism with Missense Mutations in Synaptotagmin-Like Protein 4 (SYTL4) and Transmembrane Protein 187 (TMEM187) Genes: SYTL4- Protein Modeling, Protein-Protein Interaction, Expression Profiling and MicroRNA Studies
Authors: Rafi Syed K. , Fernández-Jaén Alberto , Álvarez Sara , Nadeau Owen W. , Butler Merlin G.
Published: July 2019

We describe a 7-year-old male with high functioning autism spectrum disorder (ASD) and maternally-inherited rare missense variant of Synaptotagmin-like protein 4 (SYTL4) gene (Xq22.1; c.835C>T; p.Arg279Cys) and an unknown missense variant of Transmembrane protein 187 (TMEM187) gene (Xq28; c.708G>T; p. Gln236His). Multiple in-silico predictions described in our study indicate a potentially damaging status for both X-linked genes. Analysis of predicted atomic threading models of the mutant and the native SYTL4 proteins suggest a potential structural change induced by the R279C variant which eliminates the stabilizing Arg279-Asp60 salt bridge in the N-terminal half of the SYTL4, affecting the functionality of the protein’s critical RAB-Binding Domain. In the European (Non-Finnish) population, the allele frequency for this variant is 0.00042. The SYTL4 gene is known to directly interact with several members of the RAB family of genes, such as, RAB27A, RAB27B, RAB8A, and RAB3A which are known autism spectrum disorder genes. The SYTL4 gene also directly interacts with three known autism genes: STX1A, SNAP25 and STXBP1. Through a literature-based analytical approach, we identified three of five (60%) autism-associated serum microRNAs (miRs) with high predictive power among the total of 298 mouse Sytl4 associated/predicted microRNA interactions. Five of 13 (38%) miRs were differentially expressed in serum from ASD individuals which were predicted to interact with the mouse equivalent Sytl4 gene. TMEM187 gene, like SYTL4, is a protein-coding gene that belongs to a group of genes which host microRNA genes in their introns or exons. The novel Q236H amino acid variant in the TMEM187 in our patient is near the terminal end region of the protein which is represented by multiple sequence alignments and hidden Markov models, preventing comparative structural analysis of the variant harboring region. Like SYTL4, the TMEM187 gene is expressed in the brain and interacts with four known ASD genes, namely, HCFC1; TMLHE; MECP2; and GPHN. TMM187 is in linkage with MECP2, which is a well-known determinant of brain structure and size and is a well-known autism gene. Other members of the TMEM gene family, TMEM132E and TMEM132D genes are associated with bipolar and panic disorders, respectively, while TMEM231 is a known syndromic autism gene. Together, TMEM187 and SYTL4 genes directly interact with recognized important ASD genes, and their mRNAs are found in extracellular vesicles in the nervous system and stimulate target cells to translate into active protein. Our evidence shows that both these genes should be considered as candidate genes for autism. Additional biological testing is warranted to further determine the pathogenicity of these gene variants in the causation of autism.
Metabolomic Studies of Tissue Injury in Nonhuman Primates Exposed to Gamma-Radiation
Authors: Cheema Amrita K. , Mehta Khyati Y. , Rajagopal Meena U. , Wise Stephen Y. , Fatanmi Oluseyi O. , Singh Vijay K.
Published: July 2019

Exposure to ionizing radiation induces a complex cascade of systemic and tissue-specific responses that lead to functional impairment over time in the surviving population. However, due to the lack of predictive biomarkers of tissue injury, current methods for the management of survivors of radiation exposure episodes involve monitoring of individuals over time for the development of adverse clinical symptoms and death. Herein, we report on changes in metabolomic and lipidomic profiles in multiple tissues of nonhuman primates (NHPs) that were exposed to a single dose of 7.2 Gy whole-body 60Co γ-radiation that either survived or succumbed to radiation toxicities over a 60-day period. This study involved the delineation of the radiation effects in the liver, kidney, jejunum, heart, lung, and spleen. We found robust metabolic changes in the kidney and liver and modest changes in other tissue types at the 60-day time point in a cohort of NHPs. Remarkably, we found significant elevation of long-chain acylcarnitines in animals that were exposed to radiation across multiple tissue types underscoring the role of this class of metabolites as a generic indicator of radiation-induced normal tissue injury. These studies underscore the utility of a metabolomics approach for delineating anticipatory biomarkers of exposure to ionizing radiation.
Genetic Structure Analysis of a Collection of Tunisian Durum Wheat Germplasm
Authors: Slim Amine , Piarulli Luciana , Chennaoui Kourda Houda , Rouaissi Mustapha , Robbana Cyrine , Chaabane Ramzi , Pignone Domenico , Montemurro Cinzia , Mangini Giacomo
Published: July 2019

The Tunisian durum wheat germplasm includes modern cultivars and traditional varieties that are still cultivated in areas where elite cultivars or intensive cultivation systems are not suitable. Within the frame of a collection program of the National Gene Bank of Tunisia (NGBT), durum wheat germplasm was collected from different Tunisian agro-ecological zones. The collected samples were studied using simple sequence repeats (SSRs) markers to explore the genetic diversity and evaluate the genetic structure in Tunisian germplasm. The results demonstrated significant diversity in the Tunisian durum wheat germplasm, with clear differentiation between traditional varieties and modern cultivars. The population structure analysis allowed the identification of five subpopulations, two of which appear to be more strongly represented in germplasm collected in central and southern Tunisia, where environmental conditions at critical development phases of the plant are harsher. Moreover these subpopulations are underrepresented in modern varieties, suggesting that traits of adaptation useful for breeding more resilient varieties might be present in central and southern germplasm. Moreover, our results will support, the activity of in situ on farm conservation of Tunisian durum wheat germplasm started by the National Gene Bank of Tunisia along with the ex situ approach.
Integrated Approach Reveals Role of Mitochondrial Germ-Line Mutation F18L in Respiratory Chain, Oxidative Alterations, Drug Sensitivity, and Patient Prognosis in Glioblastoma
Authors: Keatley Kathleen , Stromei-Cleroux Samuel , Wiltshire Tammy , Rajala Nina , Burton Gary , Holt William V. , Littlewood D. Timothy J. , Briscoe Andrew G. , Jung Josephine , Ashkan Keyoumars , Heales Simon J. , Pilkington Geoffrey J. , Meunier Brigitte , McGeehan John E. , Hargreaves Iain P. , McGeehan Rhiannon E.
Published: July 2019

Glioblastoma is the most common and malignant primary brain tumour in adults, with a dismal prognosis. This is partly due to considerable inter- and intra-tumour heterogeneity. Changes in the cellular energy-producing mitochondrial respiratory chain complex (MRC) activities are a hallmark of glioblastoma relative to the normal brain, and associate with differential survival outcomes. Targeting MRC complexes with drugs can also facilitate anti-glioblastoma activity. Whether mutations in the mitochondrial DNA (mtDNA) that encode several components of the MRC contribute to these phenomena remains underexplored. We identified a germ-line mtDNA mutation (m. 14798T > C), enriched in glioblastoma relative to healthy controls, that causes an amino acid substitution F18L within the core mtDNA-encoded cytochrome b subunit of MRC complex III. F18L is predicted to alter corresponding complex III activity, and sensitivity to complex III-targeting drugs. This could in turn alter reactive oxygen species (ROS) production, cell behaviour and, consequently, patient outcomes. Here we show that, despite a heterogeneous mitochondrial background in adult glioblastoma patient biopsy-derived cell cultures, the F18L substitution associates with alterations in individual MRC complex activities, in particular a 75% increase in MRC complex II_III activity, and a 34% reduction in CoQ10, the natural substrate for MRC complex III, levels. Downstream characterisation of an F18L-carrier revealed an 87% increase in intra-cellular ROS, an altered cellular distribution of mitochondrial-specific ROS, and a 64% increased sensitivity to clomipramine, a repurposed MRC complex III-targeting drug. In patients, F18L-carriers that received the current standard of care treatment had a poorer prognosis than non-carriers (373 days vs. 415 days, respectively). Single germ-line mitochondrial mutations could predispose individuals to differential prognoses, and sensitivity to mitochondrial targeted drugs. Thus, F18L, which is present in blood could serve as a useful non-invasive biomarker for the stratification of patients into prognostically relevant groups, one of which requires a lower dose of clomipramine to achieve clinical effect, thus minimising side-effects.
Short Tandem Repeat Expansions and RNA-Mediated Pathogenesis in Myotonic Dystrophy
Authors: Sznajder Łukasz J. , Swanson Maurice S.
Published: July 2019

Short tandem repeat (STR) or microsatellite, expansions underlie more than 50 hereditary neurological, neuromuscular and other diseases, including myotonic dystrophy types 1 (DM1) and 2 (DM2). Current disease models for DM1 and DM2 propose a common pathomechanism, whereby the transcription of mutant DMPK (DM1) and CNBP (DM2) genes results in the synthesis of CUG and CCUG repeat expansion (CUGexp, CCUGexp) RNAs, respectively. These CUGexp and CCUGexp RNAs are toxic since they promote the assembly of ribonucleoprotein (RNP) complexes or RNA foci, leading to sequestration of Muscleblind-like (MBNL) proteins in the nucleus and global dysregulation of the processing, localization and stability of MBNL target RNAs. STR expansion RNAs also form phase-separated gel-like droplets both in vitro and in transiently transfected cells, implicating RNA-RNA multivalent interactions as drivers of RNA foci formation. Importantly, the nucleation and growth of these nuclear foci and transcript misprocessing are reversible processes and thus amenable to therapeutic intervention. In this review, we provide an overview of potential DM1 and DM2 pathomechanisms, followed by a discussion of MBNL functions in RNA processing and how multivalent interactions between expanded STR RNAs and RNA-binding proteins (RBPs) promote RNA foci assembly.
Beyond N-Cadherin, Relevance of Cadherins 5, 6 and 17 in Cancer Progression and Metastasis
Authors: Casal J. Ignacio , Bartolomé Rubén A.
Published: July 2019

Cell-cell adhesion molecules (cadherins) and cell-extracellular matrix adhesion proteins (integrins) play a critical role in the regulation of cancer invasion and metastasis. Although significant progress has been made in the characterization of multiple members of the cadherin superfamily, most of the published work continues to focus in the switch E-/N-cadherin and its role in the epithelial–mesenchymal transition. Here, we will discuss the structural and functional properties of a subset of cadherins (cadherin 17, cadherin 5 and cadherin 6) that have an RGD motif in the extracellular domains. This RGD motif is critical for the interaction with α2β1 integrin and posterior integrin pathway activation in cancer metastatic cells. However, other signaling pathways seem to be affected by RGD cadherin interactions, as will be discussed. The range of solid tumors with overexpression or “de novo” expression of one or more of these three cadherins is very wide (gastrointestinal, gynaecological and melanoma, among others), underscoring the relevance of these cadherins in cancer metastasis. Finally, we will discuss different evidences that support the therapeutic use of these cadherins by blocking their capacity to work as integrin ligands in order to develop new cures for metastatic patients.
Glut 1 in Cancer Cells and the Inhibitory Action of Resveratrol as A Potential Therapeutic Strategy
Authors: Zambrano Angara , Molt Matías , Uribe Elena , Salas Mónica
Published: July 2019

An important hallmark in cancer cells is the increase in glucose uptake. GLUT1 is an important target in cancer treatment because cancer cells upregulate GLUT1, a membrane protein that facilitates the basal uptake of glucose in most cell types, to ensure the flux of sugar into metabolic pathways. The dysregulation of GLUT1 is associated with numerous disorders, including cancer and metabolic diseases. There are natural products emerging as a source for inhibitors of glucose uptake, and resveratrol is a molecule of natural origin with many properties that acts as antioxidant and antiproliferative in malignant cells. In the present review, we discuss how GLUT1 is involved in the general scheme of cancer cell metabolism, the mechanism of glucose transport, and the importance of GLUT1 structure to understand the inhibition process. Then, we review the current state-of-the-art of resveratrol and other natural products as GLUT1 inhibitors, focusing on those directed at treating different types of cancer. Targeting GLUT1 activity is a promising strategy for the development of drugs aimed at treating neoplastic growth.
Protective Effects of Euthyroidism Restoration on Mitochondria Function and Quality Control in Cardiac Pathophysiology
Authors: Forini Francesca , Nicolini Giuseppina , Kusmic Claudia , Iervasi Giorgio
Published: July 2019

Mitochondrial dysfunctions are major contributors to heart disease onset and progression. Under ischemic injuries or cardiac overload, mitochondrial-derived oxidative stress, Ca2+ dis-homeostasis, and inflammation initiate cross-talking vicious cycles leading to defects of mitochondrial DNA, lipids, and proteins, concurrently resulting in fatal energy crisis and cell loss. Blunting such noxious stimuli and preserving mitochondrial homeostasis are essential to cell survival. In this context, mitochondrial quality control (MQC) represents an expanding research topic and therapeutic target in the field of cardiac physiology. MQC is a multi-tier surveillance system operating at the protein, organelle, and cell level to repair or eliminate damaged mitochondrial components and replace them by biogenesis. Novel evidence highlights the critical role of thyroid hormones (TH) in regulating multiple aspects of MQC, resulting in increased organelle turnover, improved mitochondrial bioenergetics, and the retention of cell function. In the present review, these emerging protective effects are discussed in the context of cardiac ischemia-reperfusion (IR) and heart failure, focusing on MQC as a strategy to blunt the propagation of connected dangerous signaling cascades and limit adverse remodeling. A better understanding of such TH-dependent signaling could provide insights into the development of mitochondria-targeted treatments in patients with cardiac disease.
Cellular Responses to Proteasome Inhibition: Molecular Mechanisms and Beyond
Authors: Albornoz Nicolas , Bustamante Hianara , Soza Andrea , Burgos Patricia
Published: July 2019

Proteasome inhibitors have been actively tested as potential anticancer drugs and in the treatment of inflammatory and autoimmune diseases. Unfortunately, cells adapt to survive in the presence of proteasome inhibitors activating a variety of cell responses that explain why these therapies have not fulfilled their expected results. In addition, all proteasome inhibitors tested and approved by the FDA have caused a variety of side effects in humans. Here, we describe the different types of proteasome complexes found within cells and the variety of regulators proteins that can modulate their activities, including those that are upregulated in the context of inflammatory processes. We also summarize the adaptive cellular responses activated during proteasome inhibition with special emphasis on the activation of the Autophagic-Lysosomal Pathway (ALP), proteaphagy, p62/SQSTM1 enriched-inclusion bodies, and proteasome biogenesis dependent on Nrf1 and Nrf2 transcription factors. Moreover, we discuss the role of IRE1 and PERK sensors in ALP activation during ER stress and the involvement of two deubiquitinases, Rpn11 and USP14, in these processes. Finally, we discuss the aspects that should be currently considered in the development of novel strategies that use proteasome activity as a therapeutic target for the treatment of human diseases.
Sphingosine-1-Phosphate Facilitates Skin Wound Healing by Increasing Angiogenesis and Inflammatory Cell Recruitment with Less Scar Formation
Authors: Aoki Masayo , Aoki Hiroaki , Mukhopadhyay Partha , Tsuge Takuya , Yamamoto Hirofumi , Matsumoto Noriko M. , Toyohara Eri , Okubo Yuri , Ogawa Rei , Takabe Kazuaki
Published: July 2019

Wound healing starts with the recruitment of inflammatory cells that secrete wound-related factors. This step is followed by fibroblast activation and tissue construction. Sphingosine-1-phosphate (S1P) is a lipid mediator that promotes angiogenesis, cell proliferation, and attracts immune cells. We investigated the roles of S1P in skin wound healing by altering the expression of its biogenic enzyme, sphingosine kinase-1 (SphK1). The murine excisional wound splinting model was used. Sphingosine kinase-1 (SphK1) was highly expressed in murine wounds and that SphK1−/− mice exhibit delayed wound closure along with less angiogenesis and inflammatory cell recruitment. Nanoparticle-mediated topical SphK1 overexpression accelerated wound closure, which associated with increased angiogenesis, inflammatory cell recruitment, and various wound-related factors. The SphK1 overexpression also led to less scarring, and the interaction between transforming growth factor (TGF)-β1 and S1P receptor-2 (S1PR2) signaling is likely to play a key role. In summary, SphK1 play important roles to strengthen immunity, and contributes early wound healing with suppressed scarring. S1P can be a novel therapeutic molecule with anti-scarring effect in surgical, trauma, and chronic wound management.
Inhibition of Phosphatidylinositol 3-kinase (PI3K) Signaling Synergistically Potentiates Antitumor Efficacy of Paclitaxel and Overcomes Paclitaxel-Mediated Resistance in Cervical Cancer
Authors: Liu Jing Jing , Ho Jung Yoon , Lee Hye Won , Baik Min Wha , Kim Oyoung , Choi Youn Jin , Hur Soo Young
Published: July 2019

Acquired paclitaxel (PTX) resistance limits its effectiveness and results in advanced cancer progression. This review investigated whether the inhibition of phosphatidylinositol 3-kinase (PI3K) signaling overcomes paclitaxel resistance in cervical cancer. It was established paclitaxel-resistant cell lines (PTX-R ME180/PTX-R HeLa) and determined the combination index for paclitaxel and PI3K inhibitors (BYL-719/ LY294002) by tetrazolium dye assay. Flow cytometry was used to detect the cell cycle and apoptosis. Migration and invasion were explored by wound healing and transwell assays. Genes related to multiple pathways were assessed by a western blot. It was found that the PI3K pathway was significantly activated in paclitaxel-resistant HeLa and ME180 cells compared to parental cells. PTX + PI3K inhibitor combined therapy showed a synergistic effect by strengthening paclitaxel-induced S and G2M arrest in PTX-R cell sublines by the inactivation of cyclin A1, cyclin B1, cyclin E, and Cdc2 expression. Moreover, combination therapy significantly enhanced drug sensitivity and apoptosis through the activation of Bax, and cleavage of poly-(ADP-ribose) polymerase compared with paclitaxel alone. In addition, PI3K inhibition also suppressed tumor migration and invasion by targeting β-catenin and matrix metalloproteinase-2/9. The authors suggest that the combination of a PI3K inhibitor with paclitaxel may enhance antitumor activity through a cascade of PI3K signaling events.
A Method for Improving the Accuracy and Efficiency of Bacteriophage Genome Annotation
Authors: Salisbury Alicia , Tsourkas Philippos K.
Published: July 2019

Bacteriophages are the most numerous entities on Earth. The number of sequenced phage genomes is approximately 8000 and increasing rapidly. Sequencing of a genome is followed by annotation, where genes, start codons, and functions are putatively identified. The mainstays of phage genome annotation are auto-annotation programs such as Glimmer and GeneMark. Due to the relatively small size of phage genomes, many groups choose to manually curate auto-annotation results to increase accuracy. An additional benefit of manual curation of auto-annotated phage genomes is that the process is amenable to be performed by students, and has been shown to improve student recruitment to the sciences. However, despite its greater accuracy and pedagogical value, manual curation suffers from high labor cost, lack of standardization and a degree of subjectivity in decision making, and susceptibility to mistakes. Here, we present a method developed in our lab that is designed to produce accurate annotations while reducing subjectivity and providing a degree of standardization in decision-making. We show that our method produces genome annotations more accurate than auto-annotation programs while retaining the pedagogical benefits of manual genome curation.
Identification of Human Enzymes Oxidizing the Anti-Thyroid-Cancer Drug Vandetanib and Explanation of the High Efficiency of Cytochrome P450 3A4 in its Oxidation
Authors: Indra Radek , Pompach Petr , Martínek Václav , Takácsová Paulína , Vavrová Katarína , Heger Zbyněk , Adam Vojtěch , Eckschlager Tomáš , Kopečková Kateřina , Arlt Volker Manfred , Stiborová Marie
Published: July 2019

The metabolism of vandetanib, a tyrosine kinase inhibitor used for treatment of symptomatic/progressive medullary thyroid cancer, was studied using human hepatic microsomes, recombinant cytochromes P450 (CYPs) and flavin-containing monooxygenases (FMOs). The role of CYPs and FMOs in the microsomal metabolism of vandetanib to N-desmethylvandetanib and vandetanib-N-oxide was investigated by examining the effects of CYP/FMO inhibitors and by correlating CYP-/FMO-catalytic activities in each microsomal sample with the amounts of N-desmethylvandetanib/vandetanib-N-oxide formed by these samples. CYP3A4/FMO-activities significantly correlated with the formation of N-desmethylvandetanib/ vandetanib-N-oxide. Based on these studies, most of the vandetanib metabolism was attributed to N-desmethylvandetanib/vandetanib-N-oxide to CYP3A4/FMO3. Recombinant CYP3A4 was most efficient to form N-desmethylvandetanib, while FMO1/FMO3 generated N-oxide. Cytochrome b5 stimulated the CYP3A4-catalyzed formation of N-desmethylvandetanib, which is of great importance because CYP3A4 is not only most efficient in generating N-desmethylvandetanib, but also most significant due to its high expression in human liver. Molecular modeling indicated that binding of more than one molecule of vandetanib into the CYP3A4-active center can be responsible for the high efficiency of CYP3A4 N-demethylating vandetanib. Indeed, the CYP3A4-mediated reaction exhibits kinetics of positive cooperativity and this corresponded to the in silico model, where two vandetanib molecules were found in CYP3A4-active center.
Mast Cells in Cardiovascular Disease: From Bench to Bedside
Authors: Hermans M. A. W. , Roeters van Lennep J. E. , van Daele P. L. A. , Bot I.
Published: July 2019

Mast cells are pluripotent leukocytes that reside in the mucosa and connective tissue. Recent studies show an increased prevalence of cardiovascular disease among patients with mastocytosis, which is a hematological disease that is characterized by the accumulation of mast cells due to clonal proliferation. This association suggests an important role for mast cells in cardiovascular disease. Indeed, the evidence establishing the contribution of mast cells to the development and progression of atherosclerosis is continually increasing. Mast cells may contribute to plaque formation by stimulating the formation of foam cells and causing a pro-inflammatory micro-environment. In addition, these cells are able to promote plaque instability by neo-vessel formation and also by inducing intraplaque hemorrhage. Furthermore, mast cells appear to stimulate the formation of fibrosis after a cardiac infarction. In this review, the available data on the role of mast cells in cardiovascular disease are summarized, containing both in vitro research and animal studies, followed by a discussion of human data on the association between cardiovascular morbidity and diseases in which mast cells are important: Kounis syndrome, mastocytosis and allergy.
Contracting for Road Maintenance in the Netherlands—The Downside of Performance-Based Contracting
Authors: Gelderman Cees J. , Semeijn Janjaap , De Vries Sjerp
Published: July 2019

A trend towards performance-based contracting (PBC) can be observed in public infrastructure maintenance. PBC is an approach of tying the contractor’s payment to specified performance. We investigated PBC for the maintenance of highways and roads in the Netherlands, identifying issues ultimately resulting in poor contractor performance. The PBC-induced risks for clients relate to the problematic translation and measurement of specifications, the ineffectiveness of incentives, the avoidance of contractors taking full responsibility, and contract management issues. Clients should recognize the actual balance of power in the relationship with their (main) contractors, and take appropriate measures.
Artificial Intelligence Prediction Model for the Cost and Mortality of Renal Replacement Therapy in Aged and Super-Aged Populations in Taiwan
Authors: Lin Shih-Yi , Hsieh Meng-Hsuen , Lin Cheng-Li , Hsieh Meng-Ju , Hsu Wu-Huei , Lin Cheng-Chieh , Hsu Chung Y. , Kao Chia-Hung
Published: July 2019

Background: Prognosis of the aged population requiring maintenance dialysis has been reportedly poor. We aimed to develop prediction models for one-year cost and one-year mortality in aged individuals requiring dialysis to assist decision-making for deciding whether aged people should receive dialysis or not. Methods: We used data from the National Health Insurance Research Database (NHIRD). We identified patients first enrolled in the NHIRD from 2000–2011 for end-stage renal disease (ESRD) who underwent regular dialysis. A total of 48,153 Patients with ESRD aged ≥65 years with complete age and sex information were included in the ESRD cohort. The total medical cost per patient (measured in US dollars) within one year after ESRD diagnosis was our study’s main outcome variable. We were also concerned with mortality as another outcome. In this study, we compared the performance of the random forest prediction model and of the artificial neural network prediction model for predicting patient cost and mortality. Results: In the cost regression model, the random forest model outperforms the artificial neural network according to the mean squared error and mean absolute error. In the mortality classification model, the receiver operating characteristic (ROC) curves of both models were significantly better than the null hypothesis area of 0.5, and random forest model outperformed the artificial neural network. Random forest model outperforms the artificial neural network models achieved similar performance in the test set across all data. Conclusions: Applying artificial intelligence modeling could help to provide reliable information about one-year outcomes following dialysis in the aged and super-aged populations; those with cancer, alcohol-related disease, stroke, chronic obstructive pulmonary disease (COPD), previous hip fracture, osteoporosis, dementia, and previous respiratory failure had higher medical costs and a high mortality rate.
Identification of Retinal Biomarkers in Alzheimer’s Disease Using Optical Coherence Tomography: Recent Insights, Challenges, and Opportunities
Authors: Cabrera DeBuc Delia , Gaca-Wysocka Magdalena , Grzybowski Andrzej , Kanclerz Piotr
Published: July 2019

This review will highlight recent insights into measuring retinal structure in Alzheimer’s disease (AD). A growing body of evidence indicates that disturbances in retinal blood flow and structure are related to cognitive function, which can severely impair vision. Optical coherence tomography (OCT) is an optical imaging technology that may allow researchers and physicians to gain deeper insights into retinal morphology and clarify the impact of AD on retinal health and function. Direct and noninvasive measurement of retinal morphology using OCT has provided useful diagnostic and therapeutic indications in several central nervous system (CNS) diseases, including AD, multiple sclerosis, and Parkinson disease. Despite several limitations, morphology assessment in the retinal layers is a significant advancement in the understanding of ocular diseases. Nevertheless, additional studies are required to validate the use of OCT in AD and its complications in the eye.
Exploration of Artificial Intelligence Use with ARIES in Multiple Myeloma Research
Authors: Loda Sophia , Krebs Jonathan , Danhof Sophia , Schreder Martin , Solimando Antonio G. , Strifler Susanne , Rasche Leo , Kortüm Martin , Kerscher Alexander , Knop Stefan , Puppe Frank , Einsele Hermann , Bittrich Max
Published: July 2019

Background: Natural language processing (NLP) is a powerful tool supporting the generation of Real-World Evidence (RWE). There is no NLP system that enables the extensive querying of parameters specific to multiple myeloma (MM) out of unstructured medical reports. We therefore created a MM-specific ontology to accelerate the information extraction (IE) out of unstructured text. Methods: Our MM ontology consists of extensive MM-specific and hierarchically structured attributes and values. We implemented “A Rule-based Information Extraction System” (ARIES) that uses this ontology. We evaluated ARIES on 200 randomly selected medical reports of patients diagnosed with MM. Results: Our system achieved a high F1-Score of 0.92 on the evaluation dataset with a precision of 0.87 and recall of 0.98. Conclusions: Our rule-based IE system enables the comprehensive querying of medical reports. The IE accelerates the extraction of data and enables clinicians to faster generate RWE on hematological issues. RWE helps clinicians to make decisions in an evidence-based manner. Our tool easily accelerates the integration of research evidence into everyday clinical practice.
Increased Lymphangiogenesis and Lymphangiogenic Growth Factor Expression in Perivascular Adipose Tissue of Patients with Coronary Artery Disease
Authors: Drosos Ioannis , Pavlaki Maria , Ortega Carrillo Maria , Kourkouli Adriani , Buschmann Katja , Konstantinou Fotios , Gogiraju Rajinikanth , Bochenek Magdalena , Chalikias Georgios , Tortopidis Christos , Vahl Christian , Mikroulis Dimitrios , Tziakas Dimitrios , Münzel Thomas , Konstantinides Stavros , Schäfer Katrin
Published: July 2019

Experimental and human autopsy studies have associated adventitial lymphangiogenesis with atherosclerosis. An analysis of perivascular lymphangiogenesis in patients with coronary artery disease is lacking. Here, we examined lymphangiogenesis and its potential regulators in perivascular adipose tissue (PVAT) surrounding the heart (C-PVAT) and compared it with PVAT of the internal mammary artery (IMA-PVAT). Forty-six patients undergoing coronary artery bypass graft surgery were included. Perioperatively collected C-PVAT and IMA-PVAT were analyzed using histology, immunohistochemistry, real time PCR, and PVAT-conditioned medium using cytokine arrays. C-PVAT exhibited increased PECAM-1 (platelet endothelial cell adhesion molecule 1)-positive vessel density. The number of lymphatic vessels expressing lymphatic vessel endothelial hyaluronan receptor-1 or podoplanin was also elevated in C-PVAT and associated with higher inflammatory cell numbers, increased intercellular adhesion molecule 1 (ICAM1) expression, and fibrosis. Significantly higher expression of regulators of lymphangiogenesis such as vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor-3 was observed in C-PVAT compared to IMA-PVAT. Cytokine arrays identified angiopoietin-2 as more highly expressed in C-PVAT vs. IMA-PVAT. Findings were confirmed histologically and at the mRNA level. Stimulation of human lymphatic endothelial cells with recombinant angiopoietin-2 in combination with VEGF-C enhanced sprout formation. Our study shows that PVAT surrounding atherosclerotic arteries exhibits more extensive lymphangiogenesis, inflammation, and fibrosis compared to PVAT surrounding a non-diseased vessel, possibly due to local angiopoietin-2, VEGF-C, and VEGF-D overexpression.