bluuebunny/crossref_metadata_2025 huggingface dataset:
COUNSELING OF FAMILY FINANCIAL MANAGEMENT LITERACY PROGRAM KELUARGA HARAPAN BENEFICIARIES
Authors: BENI Sabinus
Published: May 2020

Community service was carried out in Setia Budi Village, Bengkayang District, West Kalimantan. The event was held on February 18, 2019 with 97 participants as Pre-Prosperous Family beneficiaries of the Hope Family Program. The purpose of this activity is that the families of the beneficiaries of the family program hope to manage their wealth well so that the assistance in the form of cash received is right on target and managed well. The method used in the form of lectures and question and answer and the practice of directly preparing the family financial budget. The results expected in this activity are to assist the government in managing family finances so that beneficiary families can graduate independently from their participation as beneficiaries of family program expectations because economy has increased.
PROMOTION OF CASSAVA CHIPS &Quot;TETTE&Quot; THROUGH INSTAGRAM AND FACEBOOK ACCOUNTS AT BUMDES MADULANG, OMBEN DISTRICT, SAMPANG REGENCY
Authors: AUGUSTINAH Fedianty
Published: May 2020

Partners in the Community Partnership Program are Madulang Village-Owned Enterprises (Bumdes) in Omben District, Sampang Regency, which is managed by the Head of Madulang Village who has managed the production of Cassava Chips known as Tette. Madum Bumdes Kripik Cassava TETTE so far only uses one of the social media namely Whattshap (WA) alone as a means of promotion to sell its products but Madum Bumdes still has not utilized the various applications that have been provided by social media either through Android Mobile or wifi facilities that are currently rife at regions / villages at this time so that it can be said that the use of promotional facilities has not been maximized using Social Media such as Instagram and Facebook which has a wider range of promotions to increase the sales volume of TETTE chips. Some things that are considered a priority issue by Bumdes Madulang partners are problems creating accounts through social media Instagram and Facebook and marketing TETTE cassava chips through social media Instagram and Facebook. The solution provided is in the form of training (coaching and mentoring) carried out with the first chronological or phased strategy that is giving knowledge / opening insights to Madulang Village Business Entrepreneurs about the importance of using Facebook and Instagram social media as a means of promoting TETTE cassava chips and the second provide training on making Facebook and Instagram accounts as a means of promoting TETTE cassava chips. The third solution activity was to produce photos and promotional videos of TETTE sigkong chips. to fill Facebook and Instagram accounts and the fourth agreed solution is to evaluate the promotion of TETTE sigkong chips that have been carried out by Madulang Village-Owned Enterprises through social media accounts Facebook and Instagram. Suggestions that can be used by several related parties to assist in the development of the business of tette chips in Bumdes Madulang, District of Omben, Sampang Regency, training for the use of social media as a means of promotion at present where training related to marketing and marketing communication through
EDUKASI “SADARI” (PERIKSA PAYUDARA SENDIRI) UNTUK DETEKSI DINI KANKER PAYUDARA DI KELURAHAN CIPAYUNG KOTA DEPOK
Authors: PULUNGAN Rafiah Maharani , HARDY Fathinah Ranggauni
Published: May 2020

The problem of breast cancer and the impact it has created will require public health interventions in the form of a national countermeasure program regulated in Permenkes No. 34 of 2015 concerning Management of Breast Cancer and Cervical Cancer. One of the prevention of breast cancer is case finding with early detection which is done through Breast Self-Examination (BSE) which can be done easily which aims to determine the presence or absence of a lump that can develop into breast cancer.

One of the prevention of breast cancer is case finding with early detection which is done through Breast Self-Examination (BSE) which can be done easily which aims to determine the presence or absence of a lump that can develop into breast cancer.  The purpose of this activity is to increase knowledge, and change behavior about early detection of breast cancer through Breast Self-Examination (BSE) in Cipayung Village, Depok City. The target audience for this service is the Health Officers and Cadres in the Puskesmas, and especially the mothers in Cipayung Village. The method of implementation of this community service includes the preparation, implementation and evaluation stages. In the preparation stage it was shown that all participants had never received education about BSE before, even 95% of the 32 participants had just heard about BSE. Low initial knowledge can be seen from the results of pre-tests conducted in which the majority of mothers' level of knowledge is still low about breast self-examination and breast cancer after education and training there is an increase in maternal knowledge about breast self-examination. It is recommended that health workers regularly provide education about breast self-awareness to women, especially mothers.
ABOUT THE IMPLEMENTATION OF THE NATIONAL SYSTEM OF LABELING OF ROAD VEHICLES REGARDING LEVEL OF ENVIRONMENTAL HAZARD
Authors: Klimenko Oleksiy , Sotsky Vladimir , Shchelkunov Anton , Kyrychenko Ruslan , Ageev Vladimir , Ustymenko Viktor , Gutarevych Yurii
Published: May 2020

Key aspects, problematic issues, and the proposals for implementation of possible variant of an efficient system of labeling of road vehicles
regarding an actual level of environmental hazard (LEH) in the unified system of coordinates are considered. It is taking into account vehicle age, technical
condition and other factors, and based on available data on vehicle`s design and indicators, defined not only by the standards of the European Union
(environmental standards “Euro”) but also by the standards of other regions of the world, in particular, the North American market. The proposed system
can serve as a fundamental element in promoting the development of international trade and improving the quality of vehicle fleet upgrades in Ukraine,
reducing the tax burden on citizens during the acquisition of vehicles (which makes it possible to invest in more modern and environmentally friendly
vehicles), due to the introduction in Ukraine, similarly with the practice of EU Member States, of a differentiated and fair fiscal policy using the “polluter
pays” principle, and other instruments to encourage the use of more environmentally friendly vehicles, differentiated restrictions and preferences for access
to infrastructure, including the establishment by local communities of a flexible system of differentiated ecological zones for transport. The proposed
universal, convenient and efficient LEH system, and appropriate labeling of vehicles of all major categories, will also stimulate the creation of a system of
restoration of the ecological properties of vehicles in the country by the planned replacement of the replacement elements of the exhaust gas after-treatment
systems, stimulate the “retrofitting” with the improvement of the ecological properties vehicles being in operation, and include in the same system both
“traditional” internal combustion engines and technology of electric vehicles as well.
Keywords: road vehicles, adduced pollutant`s emissions, labeling of environmental hazard (LEH).
REDUCING OF EXTERNAL NOISE ARMED VEHICLE “DOZOR-B”
APPLICATIONS TO DUMPING COATING
Authors: Fedorov Volodymyr , Yanovsky Vasyl , Feshchenko V.O.
Published: May 2020

There has been a war in Ukraine for 6 years. In this regard, the production of military equipment has increased significantly, including. armored vehicles. Serious requirements are imposed on any military equipment. This paper focuses on the reduction of the external noise of the Dozor-B armored vehicle both in terms of ecology and in terms of camouflage. The technical characteristics of the mentioned armored car and its main sources of noise are briefly discussed. It is concluded that the body emits a significant level of noise, and therefore it is important to reduce the total external noise of the armored car by reducing the noise emitted by the body of the latter. The dissertation work of Krutolapov V.Ye. was analyzed. "A method of improving the vibroacoustic characteristics of the car body using vibration damping materials." The dissertation deals with the method of measuring the amplitude-frequency characteristic of a plate with a damping coating, called "obst". We have pointed out the disadvantages developed by Krutolapov V.Ye. bituminous coated plates and suggested their solution. A method of reducing the level of external noise of armored vehicles by coating their housings with a multilayer damping coating is proposed. The algorithm of calculation of the mentioned covering is developed. The choice of the necessary materials is made on the basis of their acoustic properties, heat resistance and cost. The number of coating layers is calculated based on the required acoustic effect, cost and weight of the structure. The acoustic efficiency of the developed three-layer damping coating was calculated, as well as the estimation of the external noise reduction of the Dozor-B armored car for a number of speeds of the latter on the main cycle on the road due to the application of this coating. Keywords: transport, armored car, armed forces, fire support machine, military equipment, engine, power unit, noise, camouflage, ecology, noise source, housing, acoustic efficiency, wave impedance, sound penetration coefficient, multi-layer vibration damping material.
TOWARDS ROAD SAFETY AUDIT ON ROAD NETWORK OF UKRAINE
Authors: Kaskiv Volodymyr , Vozniuk Andrii , Nahrebelna Liudmyla
Published: May 2020

The key role in the implementation of the state transport strategy is played by the development of transport infrastructure, the most important component of which is the road network. The compliance of highways with the requirements of modern traffic flows determines not only the efficiency of industry and agriculture, but also ensuring the proper standard of living of people and the state defense capability.
Problems of efficient functioning of public roads, urban roads and streets of Ukraine are outlined. The main provisions for the road safety audit are outlined.
Road safety audits are proven to be one of the most effective engineering tools that affect road safety. The main benefit of road safety audit is the detailed assessment of the road safety design solutions at all stages of design.
The purpose of a road safety audit is to answer the following questions:
- what road elements could pose a threat to road users: to what extent, to what road users and under what circumstances;
- what opportunities exist to eliminate or reduce the impact of identified threats on traffic safety.
The earlier an audit is carried out in the design and construction processes, the better and more useful the results are. Carrying out an audit in the early stages can help eliminate problems early and, as a consequence, minimize the time and cost of redesigning in the subsequent stages.
In addition, it should be noted that conducting an audit leads to intensive negotiations between the auditors, the customer and the designer. Such negotiations are useful for raising awareness of all stakeholders, as well as for improving day-to-day work, design procedures and will be useful for updating building standards or norms.
The questions of improvement of methods of calculation of safe speed of movement, development of algorithms of multivariate analysis of conditions of movement, identification of potentially dangerous sites and identification of causes of danger are considered.
A mechanism is provided that can significantly accelerate such an audit, effectively utilize human, time and financial resources.
Keywords: audit, algorithm, traffic safety, road, method, model, speed.
Does Thirty-Minute Standardised Training Improve the Inter-Observer Reliability of the Horse Grimace Scale (HGS)? A Case Study
Authors: Dai Francesca , Leach Matthew , MacRae Amelia Mari , Minero Michela , Dalla Costa Emanuela
Published: May 2020

The Horse Grimace Scale (HGS) is a facial-expression-based pain coding system that enables a range of acute painful conditions in horses to be effectively identified. Using valid assessment methods to identify pain in horses is of a clear importance; however, the reliability of the assessment is highly dependent on the assessors’ ability to use it. Training of new assessors plays a critical role in underpinning reliability. The aim of the study was to evaluate whether a 30-minute standardised training program on HGS is effective at improving the agreement between observers with no horse experience and when compared to an HGS expert. Two hundred and six undergraduate students with no horse experience were recruited. Prior to any training, observers were asked to score 10 pictures of horse faces using the six Facial Action Units (FAUs) of the HGS. Then, an HGS expert provided a 30-minute face-to-face training session, including detailed descriptions and example pictures of each FAU. After training, observers scored 10 different pictures. Cohen’s k coefficient was used to determine inter-observer reliability between each observer and the expert; a paired-sample t-test was conducted to determine differences in agreement pre- and post-training. Pre-training, Cohen’s k ranged from 0.20 for tension above the eye area to 0.68 for stiffly backwards ears. Post-training, the reliability for stiffly backwards ears and orbital tightening significantly increased, reaching Cohen’s k values of 0.90 and 0.91 respectively (paired-sample t-test; p < 0.001). The results suggest that this 30-minute face-to-face training session was not sufficient to allow observers without horse experience to effectively apply HGS. However, this standardised training program could represent a starting point for a more comprehensive training program for those without horse experience in order to increase their reliably in applying HGS.
Green Tea and Pomegranate Extract Administered During Critical Moments of the Production Cycle Improves Blood Antiradical Activity and Alters Cecal Microbial Ecology of Broiler Chickens
Authors: Perricone Vera , Comi Marcello , Giromini Carlotta , Rebucci Raffaella , Agazzi Alessandro , Savoini Giovanni , Bontempo Valentino
Published: May 2020

Phytobiotics are usually tested in feed and throughout the production cycle. However, it could be beneficial to evaluate their effects when administered only during critical moments, such as changes in feeding phases. The aim of the trial was to investigate the effect of a commercial plant extract (PE; IQV-10-P01, InQpharm Animal Health, Kuala Lumpur, Malaysia) on growth performance, blood antiradical activity and cecal microbiome when administered in drinking water to broiler chickens during the post-hatching phase and at each change of diet. In the experiment, 480 1-day-old male broiler chicks were assigned to two groups in a 50-day trial. Broilers received drinking water (C) or drinking water plus PE (T) at a rate of 2 mL/L on days 0 to 4, 10–11 and 20–21. PE did not affect performance and water intake, while total antiradical activity was improved (p < 0.05). A greater abundance of lactic acid bacteria (false discovery rate (FDR) < 0.05) was found in the T group and the result was confirmed at a lower taxonomic level with higher Lactobacillaceae abundance (FDR < 0.05). Our findings suggest that PE administration during critical moments of the production cycle of broiler chickens may exert beneficial effects at a systemic level and on gut microbial ecology.
Behavioral Response of Weaned Pigs during Gas Euthanasia with CO2, CO2 with Butorphanol, or Nitrous Oxide
Authors: Çavuşoğlu Enver , Rault Jean-Loup , Gates Richard , Lay Donald C.
Published: May 2020

The swine industry is often forced to euthanize pigs in the first few weeks of life due to injuries, hernias, or unthriftiness. The majority of pigs are euthanized using carbon dioxide (CO2) gas asphyxiation but concerns as to the humaneness of CO2 are increasing. This study compared the euthanasia of weaned pigs using N2O (N2O; n = 9) or CO2 (n = 9), at 50% and 25% min−1 exchange rate, respectively. In addition, we administered an analgesic prior to euthanasia with CO2 (CO2B) exposure as a third treatment (n = 9) to elucidate behaviors indicative of pain. Pigs in the CO2 and N2O treatments lost posture at similar times (latency of 145.0 ± 17.3 and 162.6 ± 7.0 s respectively, p > 0.10), while the CO2B treatment pigs lost posture the soonest (101.2 ± 4.7 s, p < 0.01). The pigs in the CO2B treatment made more escape attempts than the CO2 or N2O pigs (16.4 ± 4.2, 4.7 ± 1.6, 0.3 ± 0.2, respectively; p < 0.0004). However, pigs in N2O squealed more often than either the CO2 or CO2B pigs (9.0 ± 1.6, 2.8 ± 1.2, 1.3 ± 0.6, respectively, p < 0.001). Given the similar time to loss of posture and shorter time displaying open mouth breathing, N2O may cause less stress to pigs; however, the greater number of squeals performed by these pigs suggests the opposite. It was not apparent that any behavior measured was indicative of pain. In conclusion, N2O applied at a 50% min−1 flow rate can be an alternative to CO2 for pig euthanasia.
Dimethylglycine Supplementation in Reduced Energy Broilers’ Diets Restores Performance by Improving Nutrient Digestibility
Authors: Chalvatzi Sofia , Papadopoulos Georgios A. , Tsiouris Vasilios , Giannenas Ilias , Karapanagiotidis Ioannis T. , Theodoridis Alexandros , Georgopoulou Ioanna , Fortomaris Paschalis D.
Published: May 2020

Reducing the energy content of broiler diets could lead to the formulation of diets with reduced production cost. Dimethylgycine (DMG) has been used as a dietary supplement to enhance dietary fat utilization in poultry. The objective of the present study was to investigate the effects of DMG supplementation in reduced energy diets on performance and nutrient digestibility in broiler chickens. Four hundred and eighty day-old broilers were randomly allocated to three dietary treatments: a standard energy diet (PC treatment), a reduced energy diet by 66 kcal/kg (NC treatment) and the reduced energy diet supplemented with 500 mg/kg of DMG (DMG treatment). Fat digestibility was significantly higher in DMG group, compared to PC and NC groups. Intestines and gizzard lesion scores were found to be lower in the DMG group compared to PC. DMG supplementation resulted in lower jejunum pH and ileum viscosity in broilers. Overall, the present study showed that DMG supplementation in reduced energy broiler diets restored growth performance to the levels obtained with a standard diet. This result was probably mediated by the positive effects on the gastrointestinal function of the broilers after DMG supplementation, as evidenced by the improved nutrient digestibility, the reduced gross lesion scores and the lower values in intestinal pH and viscosity.
Genetic Parameters and Inbreeding Effect of Morphological Traits in Sardinian Anglo Arab Horse
Authors: Giontella Andrea , Sarti Francesca Maria , Biggio Giovanni Paolo , Giovannini Samira , Cherchi Raffaele , Pieramati Camillo , Silvestrelli Maurizio
Published: May 2020

The purpose of this study was to estimate the heritability and genetic correlations of four biometric measurements and an overall score (OS) in the Sardinian Anglo-Arab horse (SAA); moreover, the effect of inbreeding on these traits was investigated. A dataset with 43,624 horses (27,052 females and 16,572 males) was provided by the Agricultural Research Agency of Sardinia (AGRIS). Cannon bone circumference (BC), chest girth (CG), shoulder length (SL), and withers height (WH) were measured on 6033 SAA horses born in Sardinia between 1967 and 2005; beside the measurements, an overall score (OS) was taken comparing the morphology of each horse to an “ideal type” that is scored out of 100. The mean value is 20.5 cm for BC, 185.9 cm for CG, 67.6 cm for SL, 160.8 cm for WH, and 73.2 for the OS. The heritability estimates ranged from 0.78 to 0.23. The results allow to foresee high genetic progress through the breeding programs. The most affected trait by the inbreeding rate seems to only be the withers height.
Urinary Pharmacokinetic and Pharmacodynamic Profiles of Fosfomycin against Extended-Spectrum β-Lactamase-Producing Escherichia coli with Canine Ex Vivo Modeling: A Pilot Study
Authors: Harada Kazuki , Shimizu Takae , Kawaguchi Koji , Furuhashi Takeshi , Ishihara Genki
Published: May 2020

Fosfomycin is a candidate drug for extended-spectrum β-lactamase (ESBL)-producing bacteria, but its efficacy is yet to be investigated in dogs. This study investigated the urinary pharmacokinetic/pharmacodynamic (PK/PD) profile of fosfomycin orally administered at 80 mg/kg to six healthy dogs to assess its efficacy for canine urinary tract infections (UTIs) caused by ESBL-producing bacteria. Four strains of ESBL-producing Escherichia coli (ESBL-EC) characterized by fosfomycin minimum inhibitory concentrations (MICs) of 0.5, 1, 2, and 32 µg/mL were used. Urine samples for the measurement of urinary drug concentrations and urinary bactericidal titers (UBTs) were obtained after drug administration. The urinary concentrations (µg/mL, mean ± SE) were 1348.2 ± 163.5, 1191.6 ± 260.2, and 661.1 ± 190.4 at 0–4, 4–8, and 8–12 h, respectively, after drug administration. The mean urinary area under the curve during the test period (AUC0–12) of fosfomycin was estimated to be 12,803.8 µg·h/mL. The UBTs for all tested strains fluctuated closely with urine concentration during the test period (r = 0.944–1.000), and the area under the UBT-versus-time curve correlated with the urinary AUC/MIC of each strain (r = 0.991). According to the optimal urinary PK/PD target value, fosfomycin at 80 mg/kg twice daily may be suitable for the treatment of canine UTIs caused by ESBL-EC presenting MIC ≤ 128 µg/mL.
Differentiation of Murine C2C12 Myoblasts Strongly Reduces the Effects of Myostatin on Intracellular Signaling
Authors: Lautaoja Juulia H. , Pekkala Satu , Pasternack Arja , Laitinen Mika , Ritvos Olli , Hulmi Juha J.
Published: May 2020

Alongside in vivo models, a simpler and more mechanistic approach is required to study the effects of myostatin on skeletal muscle because myostatin is an important negative regulator of muscle size. In this study, myostatin was administered to murine (C2C12) and human (CHQ) myoblasts and myotubes. Canonical and noncanonical signaling downstream to myostatin, related ligands, and their receptor were analyzed. The effects of tumorkines were analyzed after coculture of C2C12 and colon cancer-C26 cells. The effects of myostatin on canonical and noncanonical signaling were strongly reduced in C2C12 cells after differentiation. This may be explained by increased follistatin, an endogenous blocker of myostatin and altered expression of activin receptor ligands. In contrast, CHQ cells were equally responsive to myostatin, and follistatin remained unaltered. Both myostatin administration and the coculture stimulated pathways associated with inflammation, especially in C2C12 cells. In conclusion, the effects of myostatin on intracellular signaling may be cell line- or organism-specific, and C2C12 myotubes seem to be a nonoptimal in vitro model for investigating the effects of myostatin on canonical and noncanonical signaling in skeletal muscle. This may be due to altered expression of activin receptor ligands and their regulators during muscle cell differentiation.
Cystathionine-β-synthase: Molecular Regulation and Pharmacological Inhibition
Authors: Zuhra Karim , Augsburger Fiona , Majtan Tomas , Szabo Csaba
Published: May 2020

Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen sulfide (H2S), a gaseous biological mediator with multiple regulatory roles in the vascular, nervous, and immune system. CBS is up-regulated in several diseases, including Down syndrome and many forms of cancer; in these conditions, the preclinical data indicate that inhibition or inactivation of CBS exerts beneficial effects. This article overviews the current information on the expression, tissue distribution, physiological roles, and biochemistry of CBS, followed by a comprehensive overview of direct and indirect approaches to inhibit the enzyme. Among the small-molecule CBS inhibitors, the review highlights the specificity and selectivity problems related to many of the commonly used “CBS inhibitors” (e.g., aminooxyacetic acid) and provides a comprehensive review of their pharmacological actions under physiological conditions and in various disease models.
Exomes of Ductal Luminal Breast Cancer Patients from Southwest Colombia: Gene Mutational Profile and Related Expression Alterations
Authors: Cortes-Urrea Carolina , Bueno-Gutiérrez Fernando , Solarte Melissa , Guevara-Burbano Miguel , Tobar-Tosse Fabian , Vélez-Varela Patricia E. , Bonilla Juan Carlos , Barreto Guillermo , Velasco-Medina Jaime , Moreno Pedro A. , De Las Rivas Javier
Published: May 2020

Cancer is one of the leading causes of mortality worldwide. Breast cancer is the most frequent cancer in women, and in recent years it has become a serious public health problem in Colombia. The development of large-scale omic techniques allows simultaneous analysis of all active genes in tumor cells versus normal cells, providing new ways to discover the drivers of malignant transformations. Whole exome sequencing (WES) was obtained to provide a deep view of the mutational genomic profile in a set of cancer samples from Southwest Colombian women. WES was performed on 52 tumor samples from patients diagnosed with invasive breast cancer, which in most cases (33/52) were ductal luminal breast carcinomas (IDC-LM-BRCA). Global variant call was calculated, and six different algorithms were applied to filter out false positives and identify pathogenic variants. To compare and expand the somatic tumor variants found in the Colombian cohort, exome mutations and genome-wide expression alterations were detected in a larger set of tumor samples of the same breast cancer subtype from TCGA (that included DNA-seq and RNA-seq data). Genes with significant changes in both the mutational and expression profiles were identified, providing a set of genes and mutations associated with the etiology of ductal luminal breast cancer. This set included 19 single mutations identified as tumor driver mutations in 17 genes. Some of the genes (ATM, ERBB3, ESR1, TP53) are well-known cancer genes, while others (CBLB, PRPF8) presented driver mutations that had not been reported before. In the case of the CBLB gene, several mutations were identified in TCGA IDC-LM-BRCA samples associated with overexpression of this gene and repression of tumor suppressive activity of TGF-β pathway.
The Genoprotective Role of Naringin
Authors: Szczepaniak Oskar , Ligaj Marta , Kobus-Cisowska Joanna , Tichoniuk Mariusz , Dziedziński Marcin , Przeor Monika , Szulc Piotr
Published: May 2020

Since ancient times, fruits and edible plants have played a special role in the human diet for enhancing health and maintaining youthfulness. The aim of our work was to determine the interactions between naringin, a natural ingredient of grapefruits, and DNA using an electrochemical biosensor. Electrochemical methods allow analyzing the damages occurring in the structure of nucleic acids and their interactions with xenobiotics. Our study showed that the changes in the location of electrochemical signals and their intensity resulted from the structural alterations in DNA. The signal of adenine was affected at lower concentrations of naringin, but the signal of guanine was unaffected in the same condition. The dynamics of changes occurring in the peak height and surface of adenine related to naringin concentration was also significantly lower. The complete binding of all adenine bases present in the tested double-stranded DNA solution was observed at naringin concentrations ranging from 8.5 to 10.0 µM. At larger concentrations, this active compound exerted an oxidizing effect on DNA. However, the critical concentrations of naringin were found to be more than twice as high as the dose absorbable in an average human (4 µM). The results of our work might be helpful in the construction of electrochemical sensors for testing the content of polyphenols and would allow determining their genoprotective functionality.
Large-Scale Differential Gene Expression Transcriptomic Analysis Identifies a Metabolic Signature Shared by All Cancer Cells
Authors: Abu Rmaileh Areej , Solaimuthu Balakrishnan , Tanna Mayur , Khatib Anees , Ben Yosef Michal , Hayashi Arata , Lichtenstein Michal , Shaul Yoav D.
Published: May 2020

Cancer-dependent metabolic rewiring is often manifested by selective expression of enzymes essential for the transformed cells’ viability. However, the metabolic variations between normal and transformed cells are not fully characterized, and therefore, a systematic analysis will result in the identification of unknown cellular mechanisms crucial for tumorigenesis. Here, we applied differential gene expression transcriptome analysis to examine the changes in metabolic gene profiles between a wide range of normal tissues and cancer samples. We found that, in contrast to normal tissues which exhibit a tissue-specific expression profile, cancer samples are more homogenous despite their diverse origins. This similarity is due to a “proliferation metabolic signature” (PMS), composed of 158 genes (87 upregulated and 71 downregulated gene sets), where 143 are common to all proliferative cells but 15 are cancer specific. Intriguingly, the PMS gene set is enriched for genes encoding rate-limiting enzymes, and its upregulated set with genes associated with poor patient outcome and essential genes. Among these essential genes is ribulose-5-phosphate-3-epimerase (RPE), which encodes a pentose phosphate pathway enzyme and whose role in cancer is still unclear. Collectively, we identified a set of metabolic genes that can serve as novel cancer biomarkers and potential targets for drug development.
Oxidative Stress in DNA Repeat Expansion Disorders: A Focus on NRF2 Signaling Involvement
Authors: La Rosa Piergiorgio , Petrillo Sara , Bertini Enrico Silvio , Piemonte Fiorella
Published: May 2020

DNA repeat expansion disorders are a group of neuromuscular and neurodegenerative diseases that arise from the inheritance of long tracts of nucleotide repetitions, located in the regulatory region, introns, or inside the coding sequence of a gene. Although loss of protein expression and/or the gain of function of its transcribed mRNA or translated product represent the major pathogenic effect of these pathologies, mitochondrial dysfunction and imbalance in redox homeostasis are reported as common features in these disorders, deeply affecting their severity and progression. In this review, we examine the role that the redox imbalance plays in the pathological mechanisms of DNA expansion disorders and the recent advances on antioxidant treatments, particularly focusing on the expression and the activity of the transcription factor NRF2, the main cellular regulator of the antioxidant response.
Soluble Epoxide Hydrolase Inhibition to Face Neuroinflammation in Parkinson’s Disease: A New Therapeutic Strategy
Authors: Pallàs Mercè , Vázquez Santiago , Sanfeliu Coral , Galdeano Carles , Griñán-Ferré Christian
Published: May 2020

Neuroinflammation is a crucial process associated with the pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD). Several pieces of evidence suggest an active role of lipid mediators, especially epoxy-fatty acids (EpFAs), in the genesis and control of neuroinflammation; 14,15-epoxyeicosatrienoic acid (14,15-EET) is one of the most commonly studied EpFAs, with anti-inflammatory properties. Soluble epoxide hydrolase (sEH) is implicated in the hydrolysis of 14,15-EET to its corresponding diol, which lacks anti-inflammatory properties. Preventing EET degradation thus increases its concentration in the brain through sEH inhibition, which represents a novel pharmacological approach to foster the reduction of neuroinflammation and by end neurodegeneration. Recently, it has been shown that sEH levels increase in brains of PD patients. Moreover, the pharmacological inhibition of the hydrolase domain of the enzyme or the use of sEH knockout mice reduced the deleterious effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. This paper overviews the knowledge of sEH and EETs in PD and the importance of blocking its hydrolytic activity, degrading EETs in PD physiopathology. We focus on imperative neuroinflammation participation in the neurodegenerative process in PD and the putative therapeutic role for sEH inhibitors. In this review, we also describe highlights in the general knowledge of the role of sEH in the central nervous system (CNS) and its participation in neurodegeneration. We conclude that sEH is one of the most promising therapeutic strategies for PD and other neurodegenerative diseases with chronic inflammation process, providing new insights into the crucial role of sEH in PD pathophysiology as well as a singular opportunity for drug development.
Autologous Splenocyte Reinfusion Improves Antibody-Mediated Immune Response to the 23-Valent Pneumococcal Polysaccharide-Based Vaccine in Splenectomized Mice
Authors: Li Shengwen Calvin , Kabeer Mustafa H.
Published: May 2020

Common clinical options, currently, for necessary splenectomy are vaccinations and antibiotic prophylaxis. However, despite these two adjuncts, there still occur numerous cases of overwhelming post-splenectomy infection. To examine whether reperfusion of critical splenic lymphocytes could boost immune response, we harvested splenic lymphocytes, reperfused the autologous lymphocytes, and then administered a pneumococcal vaccine (PNEUMOVAX®23, i.e., PPSV23) in splenectomized mice. We found that splenectomy impaired the immune response in the splenectomized group compared to the non-splenectomized group; the splenectomized group with lymphocyte reinfusion had a higher response to polysaccharide vaccination based on antibody titer than the splenectomized group without lymphocyte reinfusion. The sham group with the native spleen had the most elevated antibody titer against the PPSV23 polysaccharide antigen. This may be additive, resulting from contributions of the splenic structure, along with the phagocytic function of the spleen and its constituent cells affecting the antibody response. Reinfusion of splenic lymphocytes may enhance immunity without the complications associated with splenic fragment autotransplantation, which never gained acceptance. This technique is safe and simple since the splenic lymphocytes are autologous and, therefore, not self-reactive, and very similar to autologous blood transfusion. This concept may be beneficial in cases of unavoidable splenectomy, especially in pediatric cases.
BAMBI and CHGA in Prion Diseases: Neuropathological Assessment and Potential Role as Disease Biomarkers
Authors: López-Pérez Óscar , Bernal-Martín Marcos , Hernaiz Adelaida , Llorens Franc , Betancor Marina , Otero Alicia , Toivonen Janne Markus , Zaragoza Pilar , Zerr Inga , Badiola Juan José , Bolea Rosa , Martín-Burriel Inmaculada
Published: May 2020

Prion diseases affect both animals and humans. Research in the natural animal model of the disease could help in the understanding of neuropathological mechanisms and in the development of biomarkers for human pathologies. For this purpose, we studied the expression of 10 genes involved in prion propagation in vitro in the central nervous system of scrapie-infected sheep. Dysregulated genes (BAMBI and CHGA) were further analysed in a transgenic murine model (Tg338) of scrapie, and their protein distribution was determined using immunohistochemistry and Western blot. Their potential as biomarkers was finally assessed using enzyme-linked immunosorbent assay (ELISA) in cerebrospinal fluid (CSF) of scrapie sheep and Creutzfeldt-Jakob disease (CJD) patients. Protein BAMBI was upregulated in highly affected brain areas and CHGA was overexpressed along the brain in both models. Moreover, BAMBI and CHGA immunostaining scores strongly correlated with spongiosis and microgliosis in mice. Finally, levels of BAMBI were significantly higher in the CSF of clinical sheep and CJD patients. In addition to their potential as biomarkers, our work confirms the role of BAMBI and CHGA in prion neuropathology in vivo, but besides prion replication, they seem to be involved in the characteristic neuroinflammatory response associated to prion infection.
Novel Applications of Mesenchymal Stem Cell-Derived Exosomes for Myocardial Infarction Therapeutics
Authors: Ozaki Tan Sho Joseph , Floriano Juliana Ferreria , Nicastro Laura , Emanueli Costanza , Catapano Francesco
Published: May 2020

Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity globally, representing approximately a third of all deaths every year. The greater part of these cases is represented by myocardial infarction (MI), or heart attack as it is better known, which occurs when declining blood flow to the heart causes injury to cardiac tissue. Mesenchymal stem cells (MSCs) are multipotent stem cells that represent a promising vector for cell therapies that aim to treat MI due to their potent regenerative effects. However, it remains unclear the extent to which MSC-based therapies are able to induce regeneration in the heart and even less clear the degree to which clinical outcomes could be improved. Exosomes, which are small extracellular vesicles (EVs) known to have implications in intracellular communication, derived from MSCs (MSC-Exos), have recently emerged as a novel cell-free vector that is capable of conferring cardio-protection and regeneration in target cardiac cells. In this review, we assess the current state of research of MSC-Exos in the context of MI. In particular, we place emphasis on the mechanisms of action by which MSC-Exos accomplish their therapeutic effects, along with commentary on the current difficulties faced with exosome research and the ongoing clinical applications of stem-cell derived exosomes in different medical contexts.
USP47 Promotes Tumorigenesis by Negative Regulation of p53 through Deubiquitinating Ribosomal Protein S2
Authors: Cho Jinhong , Park Jinyoung , Shin Sang Chul , Jang Mihue , Kim Jae-Hong , Kim Eunice EunKyeong , Song Eun Joo
Published: May 2020

p53 is activated in response to cellular stresses such as DNA damage, oxidative stress, and especially ribosomal stress. Although the regulations of p53 by E3 ligase and deubiquitinating enzymes (DUBs) have been described, the cellular roles of DUB associated with ribosomal stress have not been well studied. In this study, we report that Ubiquitin Specific Protease 47 (USP47) functions as an important regulator of p53. We show that ubiquitinated ribosomal protein S2 (RPS2) by Mouse double minute 2 homolog (MDM2) is deubiquitinated by USP47. USP47 inhibits the interaction between RPS2 and MDM2 thereby alleviating RPS2-mediated suppression of MDM2 under normal conditions. However, dissociation of USP47 leads to RPS2 binding to MDM2, which is required for the suppression of MDM2, consequently inducing up-regulation of the p53 level under ribosomal stress. Finally, we show that depletion of USP47 induces p53 and therefore inhibits cell proliferation, colony formation, and tumor progression in cancer cell lines and a mouse xenograft model. These findings suggest that USP47 could be a potential therapeutic target for cancer.
Plasma-Derived Extracellular Vesicles Convey Protein Signatures That Reflect Pathophysiology in Lung and Pancreatic Adenocarcinomas
Authors: Fahrmann Johannes F. , Mao Xiangying , Irajizad Ehsan , Katayama Hiroyuki , Capello Michela , Tanaka Ichidai , Kato Taketo , Wistuba Ignacio I. , Maitra Anirban , Ostrin Edwin J. , Hanash Samir M. , Vykoukal Jody
Published: May 2020

Using a combination of mass-spectrometry and aptamer array-based proteomics, we characterized the protein features of circulating extracellular vesicles (EVs) in the context of lung (LUAD) and pancreatic ductal (PDAC) adenocarcinomas. We profiled EVs isolated from conditioned media of LUAD and PDAC cell lines to identify EV-associated protein cargoes released by these cancer cell types. Analysis of the resulting data identified LUAD and PDAC specific and pan-adenocarcinoma EV protein signatures. Bioinformatic analyses confirmed enrichment of proteins annotated to vesicle-associated processes and intracellular compartments, as well as representation of cancer hallmark functions and processes. Analysis of upstream regulator networks indicated significant enrichment of TP53, MYC, TGFB1 and KRAS-driven network effectors (p = 1.69 × 10−77–2.93 × 10−49) manifest in the adenocarcinoma sEV protein cargoes. We extended these findings by profiling the proteome of EVs isolated from lung (N = 15) and pancreatic ductal (N = 6) adenocarcinoma patient plasmas obtained at time of diagnosis, along with EVs derived from matched healthy controls (N = 21). Exploration of these proteomic data revealed abundant protein features in the plasma EVs with capacity to distinguish LUAD and PDAC cases from controls, including features yielding higher performance in the plasma EV isolates relative to unfractionated plasmas.
Emerging Role of Exosomes in Diagnosis and Treatment of Infectious and Inflammatory Bowel Diseases
Authors: Larabi Anaïs , Barnich Nicolas , Nguyen Hang Thi Thu
Published: May 2020

To communicate with each other, cells release exosomes that transfer their composition, including lipids, proteins and nucleic acids, to neighboring cells, thus playing a role in various pathophysiological processes. During an infection with pathogenic bacteria, such as adherent-invasive E. coli (AIEC) associated with Crohn disease, exosomes secreted by infected cells can have an impact on the innate immune responses of surrounding cells to infection. Furthermore, inflammation can be amplified via the exosomal shuttle during infection with pathogenic bacteria, which could contribute to the development of the associated disease. Since these vesicles can be released in various biological fluids, changes in exosomal content may provide a means for the identification of non-invasive biomarkers for infectious and inflammatory bowel diseases. Moreover, evidence suggests that exosomes could be used as vaccines to prime the immune system to recognize and kill invading pathogens, and as therapeutic components relieving intestinal inflammation. Here, we summarize the current knowledge on the role of exosomes in bacterial infections and highlight their potential use as biomarkers, vaccines and conveyers of therapeutic molecules in inflammatory bowel diseases.
Mutation-Associated Phenotypic Heterogeneity in Novel and Canonical PIK3CA Helical and Kinase Domain Mutants
Authors: Ghodsinia Arman Ali , Lego J-Ann Marie T. , Garcia Reynaldo L.
Published: May 2020

Phosphatidylinositol 3-kinase, catalytic subunit alpha (PIK3CA) is an oncogene often mutated in colorectal cancer (CRC). The contribution of PIK3CA mutations in acquired resistance to anti-epidermal growth factor receptor (EGFR) therapy is well documented, but their prognostic and predictive value remain unclear. Domain- and exon-specific mutations are implicated in either favorable or poor prognoses, but there is paucity in the number of mutations characterized outside of the mutational hotspots. Here, two novel non-hotspot mutants—Q661K in exon 13 and C901R in exon 19—were characterized alongside the canonical exon 9 E545K and exon 20 H1047R mutants in NIH3T3 and HCT116 cells. Q661K and E545K both map to the helical domain, whereas C901R and H1047R map to the kinase domain. Results showed variable effects of Q661K and C901R on morphology, cellular proliferation, apoptosis resistance, and cytoskeletal reorganization, with both not having any effect on cellular migration. In comparison, E545K markedly promoted proliferation, survival, cytoskeletal reorganization, migration, and spheroid formation, whereas H1047R only enhanced the first three. In silico docking suggested these mutations negatively affect binding of the p85 alpha regulatory subunit to PIK3CA, thereby relieving PIK3CA inhibition. Altogether, these findings support intra-domain and mutation-specific variability in oncogenic readouts, with implications in degree of aggressiveness.
A Model for Estimating Dose-Rate Effects on Cell-Killing of Human Melanoma after Boron Neutron Capture Therapy
Authors: Matsuya Yusuke , Fukunaga Hisanori , Omura Motoko , Date Hiroyuki
Published: May 2020

Boron neutron capture therapy (BNCT) is a type of radiation therapy for eradicating tumor cells through a 10B(n,α)7Li reaction in the presence of 10B in cancer cells. When delivering a high absorbed dose to cancer cells using BNCT, both the timeline of 10B concentrations and the relative long dose-delivery time compared to photon therapy must be considered. Changes in radiosensitivity during such a long dose-delivery time can reduce the probability of tumor control; however, such changes have not yet been evaluated. Here, we propose an improved integrated microdosimetric-kinetic model that accounts for changes in microdosimetric quantities and dose rates depending on the 10B concentration and investigate the cell recovery (dose-rate effects) of melanoma during BNCT irradiation. The integrated microdosimetric–kinetic model used in this study considers both sub-lethal damage repair and changes in microdosimetric quantities during irradiation. The model, coupled with the Monte Carlo track structure simulation code of the Particle and Heavy Ion Transport code System, shows good agreement with in vitro experimental data for acute exposure to 60Co γ-rays, thermal neutrons, and BNCT with 10B concentrations of 10 ppm. This indicates that microdosimetric quantities are important parameters for predicting dose-response curves for cell survival under BNCT irradiations. Furthermore, the model estimation at the endpoint of the mean activation dose exhibits a reduced impact of cell recovery during BNCT irradiations with high linear energy transfer (LET) compared to 60Co γ-rays irradiation with low LET. Throughout this study, we discuss the advantages of BNCT for enhancing the killing of cancer cells with a reduced dose-rate dependency. If the neutron spectrum and the timelines for drug and dose delivery are provided, the present model will make it possible to predict radiosensitivity for more realistic dose-delivery schemes in BNCT irradiations.