bluuebunny/crossref_metadata_2025 huggingface dataset:
How Different Stocking Densities Affect Growth and Stress Status of Acipenser baerii Early Stage Larvae
Authors: Aidos Lucia , Cafiso Alessandra , Serra Valentina , Vasconi Mauro , Bertotto Daniela , Bazzocchi Chiara , Radaelli Giuseppe , Di Giancamillo Alessia
Published: July 2020

In the present study, a multidisciplinary approach was used in order to evaluate growth, muscle development, and stress status in Siberian sturgeon Acipenser baerii larvae at schooling (T1) and complete yolk sac absorption (T2), reared at three stocking densities (low, medium, and high). Larvae growth, morphological muscle development, and whole-body cortisol levels were assessed. The expression of genes involved in the growth process (igf1 and igf2), in the myogenesis (myog), and in the regulation of cellular stress (glut1, glut2, glut4, and hsp70) was analyzed using a quantitative PCR. Larvae reared at lower densities showed a higher Specific Growth Rate and showed a physiological muscle development. Cortisol levels were low and did not differ significantly, both in different time sampling and across densities, suggesting that either the considered densities are not stressors in this species in the early stages of development or the hypothalamus-pituitary-adrenal (HPA) axis is not yet fully mature. Gene expression of glut1, igf1, and igf2 showed an up-regulation in both developmental stages at all the rearing densities considered, while myog significantly up-regulated at T1 at the highest density. Considering all of the results, it would seem that lower densities should be used in these stages of development, as these showed a higher growth rate, even if it is not economically feasible in commercial hatcheries. Therefore, choosing an intermediate stocking density could be a good compromise between larval performance and economical feasibility.
Sheep and Goats Respond Differently to Feeding Strategies Directed to Improve the Fatty Acid Profile of Milk Fat
Authors: Nudda Anna , Cannas Antonello , Correddu Fabio , Atzori Alberto Stanislao , Lunesu Mondina Francesca , Battacone Gianni , Pulina Giuseppe
Published: July 2020

This bibliographic review presents and discusses the nutritional strategies able to increase the concentration of beneficial fatty acids (FA) in sheep and goat milk, and dairy products, with a particular focus on the polyunsaturated FA (PUFA), and highlights differences between the two species. In fact, by adopting appropriate feeding strategies, it is possible to markedly vary the concentration of fat in milk and improve its FA composition. These strategies are based mostly on the utilization of herbage rich in PUFA, or on the inclusion of vegetable, marine, or essential oils in the diet of lactating animals. Sheep respond more effectively than goats to the utilization of fresh herbage and to nutritional approaches that improve the milk concentration of c9,t11-conjugated linoleic acid (c9,t11-CLA) and α-linolenic acid. Dietary polyphenols can influence milk FA profile, reducing or inhibiting the activity and growth of some strains of rumen microbes involved in the biohydrogenation of PUFA. Although the effectiveness of plant secondary compounds in improving milk FA composition is still controversial, an overall positive effect has been observed on the concentration of PUFA and RA, without marked differences between sheep and goats. On the other hand, the positive effect of dietary polyphenols on the oxidative stability of milk fat appears to be more consistent.
Effects of Flaxseed Oil and Vitamin E Supplementation on Digestibility and Milk Fatty Composition and Antioxidant Capacity in Water Buffaloes
Authors: Agustinho Bruna C. , Zeoula Lucia M. , Santos Nadine W. , Machado Erica , Yoshimura Emerson H. , Ribas Jessyca C. R. , Bragatto Janaina M. , Stemposki Mariana R. , Santos Vanessa J. dos , Faciola Antonio P.
Published: July 2020

This study aimed to evaluate the effects of the supplementation of flaxseed oil and/or vitamin E on dry matter (DM) and nutrient digestibility, milk composition, fatty acid composition, and antioxidant capacity in buffalo milk. Four crossbred female dairy water buffaloes (97 ± 22 days in milk; 6.57 ± 2.2 kg of milk/day, mean ± SD) were distributed in a 4 × 4 Latin square design, with a 2 × 2 factorial arrangement (with or without flaxseed oil at 25 g/kg dry matter; with or without vitamin E at 375 IU/kg dry matter). The experimental period was divided into four periods of 21 days each (16 days for adaptation; five days for data collection). There were four treatments: control diet (no flaxseed oil and no added vitamin E); flaxseed oil diet (flaxseed oil at 25 g/kg DM); vitamin E diet (vitamin E at 375 IU/kg DM), and a combination of both flaxseed oil and vitamin E. The animals were fed total mixed ratios. For all response variables, there was no interaction between flaxseed oil and vitamin E. Flaxseed oil supplementation reduced neutral detergent fiber (NDF) and acid detergent fiber (ADF) apparent total tract digestibility, increased the n-3 fatty acid concentration in milk approximately three-fold while reducing the n-6/n-3 ratio from 9.3:1 to 2.4:1. Vitamin E supplementation increased NDF apparent total tract digestibility and milk total antioxidant capacity. Although there was no interaction between the treatments; flaxseed oil supplementation in lactating buffaloes increased polyunsaturated fatty acid, while vitamin E supplementation increased antioxidant capacity and decreased oxidation products.
Occurrence and Molecular Characteristics of Mcr-1-Positive Escherichia coli from Healthy Meat Ducks in Shandong Province of China
Authors: Liu Fengzhi , Zhang Ruihua , Yang Yupeng , Li Hanqing , Wang Jingyu , Lan Jingjing , Li Pengfei , Zhu Yanli , Xie Zhijing , Jiang Shijin
Published: July 2020

Colistin has been used as a growth promotant in livestock feed for many years. In China, mcr-1-positive Escherichia coli strains have been isolated from humans, chickens, and pigs. To date, there are few reports about the prevalence and molecular characteristics of fecal E. coli bearing mcr-1 in the meat ducks. In this study, the prevalence of mcr-1 gene was investigated among 120 fecal E. coli strains isolated from healthy meat ducks in Shandong province of China between October 2017 and February 2018. A total of nine mcr-1-containing E. coli strains were identified and two were identified as extra-intestinal pathogenic E. coli (ExPEC) among them. The clonal relationship of the nine E. coli strains was determined by multilocus sequencing typing (MLST) and pulsed field gel electrophoresis (PFGE), and the results indicated that all mcr-1-carrying isolates were clonally unrelated. Two different genetic contexts of mcr-1 were identified among these isolates. Colistin-resistant phenotype of all the isolates was successfully transferred to the recipient strains by conjugation experiments and seven transconjugants carried a single plasmid. The mcr-1 was located on three replicon plasmids: IncI2 (n = 4), IncFII (n = 2) and IncN (n = 1). Complete sequence analysis of a representative plasmid pTA9 revealed that it was strikingly similar with plasmid pMCR1-IncI2 of E. coli, plasmid pHNSHP45 of E. coli, and plasmid pWF-5-19C of Cronobacter sakazakii, implying that pTA9-like plasmids may be epidemic plasmids that mediate the spread of mcr-1 among Enterobacteriaceae. These results highlight that healthy meat duck is a potential reservoir for multidrug resistant mcr-1-containing E. coli strains.
Use of the Multivariate Discriminant Analysis for Genome-Wide Association Studies in Cattle
Authors: Manca Elisabetta , Cesarani Alberto , Gaspa Giustino , Sorbolini Silvia , Macciotta Nicolò P.P. , Dimauro Corrado
Published: July 2020

Genome-wide association studies (GWAS) are traditionally carried out by using the single marker regression model that, if a small number of individuals is involved, often lead to very few associations. The Bayesian methods, such as BayesR, have obtained encouraging results when they are applied to the GWAS. However, these approaches, require that an a priori posterior inclusion probability threshold be fixed, thus arbitrarily affecting the obtained associations. To partially overcome these problems, a multivariate statistical algorithm was proposed. The basic idea was that animals with different phenotypic values of a specific trait share different allelic combinations for genes involved in its determinism. Three multivariate techniques were used to highlight the differences between the individuals assembled in high and low phenotype groups: the canonical discriminant analysis, the discriminant analysis and the stepwise discriminant analysis. The multivariate method was tested both on simulated and on real data. The results from the simulation study highlighted that the multivariate GWAS detected a greater number of true associated single nucleotide polymorphisms (SNPs) and Quantitative trait loci (QTLs) than the single marker model and the Bayesian approach. For example, with 3000 animals, the traditional GWAS highlighted only 29 significantly associated markers and 13 QTLs, whereas the multivariate method found 127 associated SNPs and 65 QTLs. The gap between the two approaches slowly decreased as the number of animals increased. The Bayesian method gave worse results than the other two. On average, with the real data, the multivariate GWAS found 108 associated markers for each trait under study and among them, around 63% SNPs were also found in the single marker approach. Among the top 118 associated markers, 76 SNPs harbored putative candidate genes.
Supplementation of Spring Pasture with Harvested Fodder Beet Bulb Alters Rumen Fermentation and Increases Risk of Subacute Ruminal Acidosis during Early Lactation
Authors: Fleming Anita , Garrett Konagh , Froehlich Kelly , Beck Matthew , Bryant Racheal H. , Edwards Grant , Gregorini Pablo
Published: July 2020

In a cross-over design, eight rumen cannulated dairy cows were used to explore the industry-recommended method for dietary transition to fodder beet (FB: Beta vulgaris L.) on changes to rumen fermentation and pH, milk production, dry matter intake (DMI) and the risk of subacute ruminal acidosis (SARA) during early lactation. Cows were split into two groups and individually allocated a ryegrass (Lolium Perenne L.) and white clover (Trifolium repens L.) diet (HO) or the same herbage supplemented with 6 kg DM/cow of harvested fodder beet bulbs (FBH). Dietary adaptation occurred over 20 days consisting of: stage 1: gradual transition to target FB intake (days 1–12, +0.5 kg DM of FB/d); stage 2: acclimatization (days 13–17) and stage 3: post-adaption sampling (days 18–20). Response variables were analyzed as a factorial arrangement of diet and stage of adaption using a combination of ANOVA and generalized linear mixed modelling. Dietary proportion of FB represented 22, (stage 1), 32 (stage 2) and 38% (stage 3) of daily DMI. One cow during each period developed SARA from FB and the duration of low pH increased with FBH compared to the HO treatment (p < 0.01). Rumen concentrations of lactic and butyric acid increased with FBH but concentrations of acetate, propionate and total volatile fatty acids (VFA) declined by 9.3% at day 20, compared to the HO treatment (p < 0.01). Treatments did not affect milk production but total DMI with supplemented cows increased during the final stage of adaptation and feed conversion efficiency (FCE kg milk/kg DM) declined with the FBH treatment. The occurrence of SARA in 25% of animals fed FB suggest it is a high-risk supplement to animal health and further evaluation of industry-recommended methods for feeding FB at the individual- and herd-scale are needed.
Evaluation of Poultry Stunning with Low Atmospheric Pressure, Carbon Dioxide or Nitrogen Using a Single Aversion Testing Paradigm
Authors: Gent Thomas C. , Gebhardt-Henrich Sabine , Schild Sarah-Lina Aagaard , Rahman Abdulsatar Abdel , Toscano Michael J.
Published: July 2020

Low atmospheric pressure stunning (LAPS) has been suggested for use in poultry under 4 kg in the abattoir as a more humane alternative to carbon dioxide (CO2). However, there are currently no studies offering a direct comparison of the aversion between methods. Here, we trained adult female broiler breeders to relinquish a food reward by moving to another area of the gas chamber in response to aversive stimuli. They were then stunned and subsequently killed using single exposure to either CO2, N2, LAPS or medical air as a control. Birds exposed to CO2 relinquished the food reward the quickest and exhibited gasping and headshaking more than the other groups. LAPS resulted in the quickest time to loss of posture (LOP) and birds in the N2 group took the longest. Birds exposed to N2 displayed the longest duration of ataxia of any group; however, they did not show any wing-flapping prior to LOP, unlike the LAPS and CO2. Collectively these data demonstrate that both LAPS and N2 are less aversive to poultry than CO2 and may offer a significant welfare refinement for poultry killed for meat production.
The Hemodynamics of Aneurysms Treated with Flow-Diverting Stents Considering both Stent and Aneurysm/Artery Geometries
Authors: Cillo-Velasco Paulo R. , Luciano Rafaello D. , Kelly Michael E. , Peeling Lissa , Bergstrom Donald J. , Chen Xiongbiao , Malvè Mauro
Published: July 2020

Flow diverting stents are deployed to reduce the blood flow into the aneurysm, which would thereby induce thrombosis in the aneurysm sac; the stents prevent its rupture. The present study aimed to examine and quantify the impacts of different flow stents on idealized configurations of the cerebral artery. In our study, we considered a spherical sidewall aneurysm located on curved and tortuous idealized artery vessels and three stents with different porosities (70, 80 and 90%) for deployment. Using computational fluid dynamics, the local hemodynamics in the presence and absence of the stents were simulated, respectively, under the assumption that the blood flow was unsteady and non-Newtonian. The hemodynamic parameters, such as the intra-aneurysmal flow, velocity field and wall shear stress and its related indices, were examined and compared among the 12 cases simulated. The results illustrated that with the stent deployment, the intra-aneurysmal flow and the wall shear stress and its related indices were considerably modified depending on both stent and aneurysm/artery geometries, and that the intra-aneurysmal relative residence time increased rapidly with decreasing stent porosity in all the vessel configurations. These results also inform the rationale for selecting stents for treating aneurysms of different configurations.
A Theoretical Method for Evaluating the Lubrication Performance of the Meshing Pair Profiles in Water Flooded Single Screw Compressors Based on the Micro Deflecting Motion Trajectory
Authors: Li Ting , Jiang Wei , Gan Xuetao , Chen Diyi , Huang Rui , Feng Quanke
Published: July 2020

To improve the life of the meshing pair in single screw compressor (SSC), several meshing pair profiles (MPP) were proposed for raising the lubrication properties. Therefore, it is necessary to evaluate the lubrication performance of the MPPs. In this paper, an evaluation method based on micro deflecting motion trajectory (MDMT) is proposed and the theoretical model to realize MDMT is established. The model mainly contains a geometric model, a thermodynamics model, a hydrodynamic lubrication model and corresponding algorithm. With the presented method, three kinds of MPP including single straight line type (SSLT), single column type (SCT) and multi column type (MCT) have been analyzed. Obtained results show that compared to the SSLT and SCT, the MCT generates the greatest peak value of the water film pressure. The total torque applied on the gate-rotor generated by the water films decreases with the increment of the discharge pressure and increases with the machine size. The water film stiffness firstly decreases and then increases with the micro deflecting angle increasing. The water film stiffness at trailing side is always larger than that at leading side. As the discharge pressure increases, the MDMT curves approach the leading flank, and the lubrication properties get worse. With the machine size increasing, the MDMT curves move towards the trailing side and the lubrication performance is improved. Comparing to the other two MPPs, the MCT can achieve floating mesh without contact in relatively larger machines and comparably lower discharge pressure.
Bearing Fault Classification of Induction Motors Using Discrete Wavelet Transform and Ensemble Machine Learning Algorithms
Authors: Nishat Toma Rafia , Kim Jong-Myon
Published: July 2020

Bearing fault diagnosis at early stage is very significant to ensure seamless operation of induction motors in industrial environment. The identification and classification of faults helps to undertook maintenance operation in an efficient manner. This paper presents an ensemble machine learning-based fault classification scheme for induction motors (IMs) utilizing the motor current signal that uses the discrete wavelet transform (DWT) for feature extraction. Three wavelets (db4, sym4, and Haar) are used to decompose the current signal, and several features are extracted from the decomposed coefficients. In the pre-processing stage, notch filtering is used to remove the line frequency component to improve classification performance. Finally, the two ensemble machine learning (ML) classifiers random forest (RF) and extreme gradient boosting (XGBoost) are trained and tested using the extracted feature set to classify the bearing fault condition. Both classifier models demonstrate very promising results in terms of accuracy and other accepted performance indicators. Our proposed method achieves an accuracy slightly greater than 99%, which is better than other models examined for the same dataset.
Studies of the Variability of Polyphenols and Carotenoids in Different Methods Fermented Organic Leaves of Willowherb (Chamerion angustifolium (L.) Holub)
Authors: Lasinskas Marius , Jariene Elvyra , Vaitkeviciene Nijole , Kulaitiene Jurgita , Najman Katarzyna , Hallmann Ewelina
Published: July 2020

The demand for organic production is increasing worldwide. The willowherb, grown in an organic way, contributes greatly to the idea of a healthier society and clean land. Willowherb is widespread in the world and has high polyphenols, carotenoids, and antioxidant properties. The purpose of this work was to investigate the influence of solid-phase fermentation (SPF) under different conditions on the variation of polyphenols and carotenoids in the organic leaves of willowherb. The leaves were fermented for different periods of time: 24, 48, and 72 h; and in aerobic and anaerobic conditions. The evaluation of polyphenols and carotenoids was completed using high-performance liquid chromatography (HPLC), and antioxidant activity was measured with spectrophotometric method. Hierarchical cluster analysis was used to describe differences in biologically active compounds between willowherb samples. The experiment showed that the highest quantities of total phenolic acids and flavonoids were determined after 24 h under aerobic SPF, but the amountof total carotenoids was higher after 72 h anaerobic SPF, compared to control. Not-fermented willowherb leaves had a lower antioxidant activity. compared to fermented leaves. In conclusion, SPF can be used to change polyphenol and carotenoid quantities in organic leaves of willowherb.
Spatial Unmasking Effect on Speech Reception Threshold in the Median Plane
Authors: Berwick Nathan , Lee Hyunkook
Published: July 2020

This study examined whether the spatial unmasking effect operates on speech reception thresholds (SRTs) in the median plane. SRTs were measured using an adaptive staircase procedure, with target speech sentences and speech-shaped noise maskers presented via loudspeakers at −30°, 0°, 30°, 60° and 90°. Results indicated a significant median plane spatial unmasking effect, with the largest SRT gain obtained for the −30° elevation of the masker. Head-related transfer function analysis suggests that the result is associated with the energy weighting of the ear-input signal of the masker at upper-mid frequencies relative to the maskee.
Combining Internal- and External-Training-Loads to Predict Non-Contact Injuries in Soccer
Authors: Vallance Emmanuel , Sutton-Charani Nicolas , Imoussaten Abdelhak , Montmain Jacky , Perrey Stéphane
Published: July 2020

The large amount of features recorded from GPS and inertial sensors (external load) and well-being questionnaires (internal load) can be used together in a multi-dimensional non-linear machine learning based model for a better prediction of non-contact injuries. In this study we put forward the main hypothesis that the use of such models would be able to inform better about injury risks by considering the evolution of both internal and external loads over two horizons (one week and one month). Predictive models were trained with data collected by both GPS and subjective questionnaires and injury data from 40 elite male soccer players over one season. Various classification machine-learning algorithms that performed best on external and internal loads features were compared using standard performance metrics such as accuracy, precision, recall and the area under the receiver operator characteristic curve. In particular, tree-based algorithms based on non-linear models with an important interpretation aspect were privileged as they can help to understand internal and external load features impact on injury risk. For 1-week injury prediction, internal load features data were more accurate than external load features while for 1-month injury prediction, the best performances of classifiers were reached by combining internal and external load features.
Scheduling of Preventive Maintenance in Healthcare Buildings Using Markov Chain
Authors: González-Domínguez Jaime , Sánchez-Barroso Gonzalo , García-Sanz-Calcedo Justo
Published: July 2020

The optimization of maintenance in healthcare buildings reduces operating costs and contributes towards increasing the sustainability of the healthcare system. This paper proposes a tool to schedule preventive maintenance for healthcare centers using Markov chains. To this end, the authors analyzed 25 healthcare centers belonging to the three Healthcare Districts of Spain and built between 1985 and 2005. Markov chains proved useful in choosing the most suitable maintenance policies for each healthcare building without exceeding a specific degradation boundary, which enabled achieving an ideal maintenance frequency and reduced the use of resources. Markov chains have also proven useful in optimizing the periodicity of routine maintenance tasks, ensuring a suitable level of maintenance according to the frequency of the failures and reducing the cost and carbon footprint. The healthcare centers observed during the study managed to save more than 700 km of journeys, reduce emissions in its operations as a whole by 174.3 kg of CO2 per month and increase the overall efficiency of maintenance operations by 15%. This approach, therefore, renders it advisable to plan the maintenance of healthcare buildings.
An Efficient Two-Level-Partitioning-Based Double Array and Its Parallelization
Authors: Jia Lianyin , Zhang Chongde , Li Mengjuan , Chen Yinong , Liu Yong , Ding Jiaman
Published: July 2020

Trie is one of the most common data structures for string storage and retrieval. As a fast and efficient implementation of trie, double array (DA) can effectively compress strings to reduce storage spaces. However, this method suffers from the problem of low index construction efficiency. To address this problem, we design a two-level partition (TLP) framework in this paper. We first divide the dataset is into smaller lower-level partitions, and then we merge these partitions into bigger upper-level partitions using a min-heap based greedy merging algorithm (MH-GMerge). TLP has an excellent characteristic of load balancing and can be easily parallelized. We implemented two efficient parallel partitioned DAs based on TLP. Extensive experiments were carried out, and the results showed that the proposed methods can significantly improve the construction efficiency of DA and can achieve a better trade-off between construction and retrieval performance than the existing state-of-the-art methods.
Adaptive Cruise Control for Eco-Driving Based on Model Predictive Control Algorithm
Authors: Nie Zifei , Farzaneh Hooman
Published: July 2020

An adaptive cruise control (ACC) system is developed based on eco-driving for two typical car-following traffic scenes. The ACC system is designed using the model predictive control (MPC) algorithm, to obtain objectives of eco-driving, driving safety, comfortability, and tracking capability. The optimization of driving comfortability and the minimization of fuel consumption are realized in the manner of constraining the acceleration value and its variation rate, so-called the jerk, of the host vehicle. The driving safety is guaranteed by restricting the vehicle spacing always larger than minimum safe spacing from the host vehicle to the preceding vehicle. The performances of the proposed MPC-based ACC system are evaluated and compared with the conventional proportional-integral-derivative (PID) controller-based ACC system in two representative driving scenarios, through a simulation bench and an instantaneous emissions and fuel consumption model. In addition to meeting the other driving objectives mentioned above, the simulation results indicate an improvement of 13% (at the maximum) for fuel economy, which directly shows the effectiveness of the presented MPC-based ACC system.
A Mathematical Model for Reduction of Trim Loss in Cutting Reels at a Make-to-Order Paper Mill
Authors: Khan Razaullah , Pruncu Catalin Iulian , Khan Abdul Salam , Naeem Khawar , Abas Muhammad , Khalid Qazi Salman , Aziz Asnaf
Published: July 2020

One of the main issues in a paper mill is the minimization of trim loss when cutting master reels and stocked reels into reels of smaller required widths. The losses produced in trimming at a paper mill are reprocessed by using different chemicals which contributes to significant discharge of effluent to surface water and causes environmental damage. This paper presents a real-world industrial problem of production planning and cutting optimization of reels at a paper mill and differs from other cutting stock problems by considering production and cutting of master reels of flexible widths and cutting already stocked over-produced and useable leftover reels of smaller widths. The cutting process of reels is performed with a limited number of cutting knives at the winder. The problem is formulated as a linear programming model where the generation of all feasible cutting patterns determines the columns of the constraint matrix. The model is solved optimally using simplex algorithm with the objective of trim loss minimization while satisfying a set of constraints. The solution obtained is rounded in a post-optimization procedure in order to satisfy integer constraints. When tested on data from the paper mill, the results of the proposed model showed a significant reduction in trim loss and outperformed traditional exact approaches. The cutting optimization resulted in minimum losses in paper trimming and a lesser amount of paper is reprocessed to make new reels which reduced the discharge of effluent to the environment.
The Changing Paradigm for the Treatment of HER2-Positive Breast Cancer
Authors: Patel Aena , Unni Nisha , Peng Yan
Published: July 2020

For decades, HER2-positive breast cancer was associated with poor outcomes and higher mortality rates than other breast cancer subtypes. However, the advent of Trastuzumab (Herceptin) has significantly changed the treatment paradigm of patients afflicted with HER2-positive breast cancer. The discovery of newer HER2-targeted therapies, such as Pertuzumab (Perjeta), has further added to the armamentarium of treating HER2-positive breast cancers. This review highlights recent advancements in the treatment of HER2-positive diseases, including the newer HER2-targeted therapies and immunotherapies in clinical trials, which have paved (and will further update) the way for clinical practice, and become part of the standard of care in the neoadjuvant, adjuvant or metastatic setting.
Protein Arginine Methyltransferase 5 as a Therapeutic Target for KRAS Mutated Colorectal Cancer
Authors: Shifteh David , Sapir Tzuriel , Pahmer Moshe , Haimowitz Adam , Goel Sanjay , Maitra Radhashree
Published: July 2020

Nearly 45% of colorectal cancer (CRC) patients harbor a mutation in their KRAS gene for which, despite many years of research, there are still no targeted therapies available. Protein Arginine Methyltransferase 5 (PRMT5) is a transcription regulator for multiple cellular processes that is currently being tested as a potential target in several cancer types. PRMT5 has been previously shown to be overexpressed in approximately 75% of CRC patient tumor samples, as well as negatively correlated with CRC patient survival. Here, we provide evidence that PRMT5 can act as a surrogate target for mutated KRAS in CRC. Our findings show that PRMT5 expression is upregulated, as well as positively correlated with KRAS expression, in CRC patient datasets. Moreover, our results reveal that PRMT5 is further overexpressed in KRAS mutant CRC cells when compared to KRAS wild type (WT) CRC cells at both the transcriptional and translational levels. Additionally, our data demonstrate that this further overexpression of PRMT5 in the KRAS mutant CRC cells affects an even greater degree of growth inhibition, apoptosis, and cell cycle arrest, following treatment with PRMT5 inhibitor, when compared to the KRAS WT CRC cells. Our research therefore suggests for the first time that PRMT5 and KRAS may crosstalk, and thus, PRMT5 can potentially be used as a surrogate target for mutated KRAS in CRC.
Dual Inhibitory Action of a Novel AKR1C3 Inhibitor on Both Full-Length AR and the Variant AR-V7 in Enzalutamide Resistant Metastatic Castration Resistant Prostate Cancer
Authors: Kafka Mona , Mayr Fabian , Temml Veronika , Möller Gabriele , Adamski Jerzy , Höfer Julia , Schwaiger Stefan , Heidegger Isabel , Matuszczak Barbara , Schuster Daniela , Klocker Helmut , Bektic Jasmin , Stuppner Hermann , Eder Iris E.
Published: July 2020

The expanded use of second-generation antiandrogens revolutionized the treatment landscape of progressed prostate cancer. However, resistances to these novel drugs are already the next obstacle to be solved. Various previous studies depicted an involvement of the enzyme AKR1C3 in the process of castration resistance as well as in the resistance to 2nd generation antiandrogens like enzalutamide. In our study, we examined the potential of natural AKR1C3 inhibitors in various prostate cancer cell lines and a three-dimensional co-culture spheroid model consisting of cancer cells and cancer-associated fibroblasts (CAFs) mimicking enzalutamide resistant prostate cancer. One of our compounds, named MF-15, expressed strong antineoplastic effects especially in cell culture models with significant enzalutamide resistance. Furthermore, MF-15 exhibited a strong effect on androgen receptor (AR) signaling, including significant inhibition of AR activity, downregulation of androgen-regulated genes, lower prostate specific antigen (PSA) production, and decreased AR and AKR1C3 expression, indicating a bi-functional effect. Even more important, we demonstrated a persisting inhibition of AR activity in the presence of AR-V7 and further showed that MF-15 non-competitively binds within the DNA binding domain of the AR. The data suggest MF-15 as useful drug to overcome enzalutamide resistance.
TIF1 Proteins in Genome Stability and Cancer
Authors: McAvera Roisin M. , Crawford Lisa J.
Published: July 2020

Genomic instability is a hallmark of cancer cells which results in excessive DNA damage. To counteract this, cells have evolved a tightly regulated DNA damage response (DDR) to rapidly sense DNA damage and promote its repair whilst halting cell cycle progression. The DDR functions predominantly within the context of chromatin and requires the action of chromatin-binding proteins to coordinate the appropriate response. TRIM24, TRIM28, TRIM33 and TRIM66 make up the transcriptional intermediary factor 1 (TIF1) family of chromatin-binding proteins, a subfamily of the large tripartite motif (TRIM) family of E3 ligases. All four TIF1 proteins are aberrantly expressed across numerous cancer types, and increasing evidence suggests that TIF1 family members can function to maintain genome stability by mediating chromatin-based responses to DNA damage. This review provides an overview of the TIF1 family in cancer, focusing on their roles in DNA repair, chromatin regulation and cell cycle regulation.
Metastasis of Uveal Melanoma with Monosomy-3 Is Associated with a Less Glycogenetic Gene Expression Profile and the Dysregulation of Glycogen Storage
Authors: Vardanyan Siranush , Brosig Anton , Merz Hartmut , Ranjbar Mahdy , Kakkassery Vinodh , Grisanti Salvatore , Tura Aysegül
Published: July 2020

The prolonged storage of glucose as glycogen can promote the quiescence of tumor cells, whereas the accumulation of an aberrant form of glycogen without the primer protein glycogenin can induce the metabolic switch towards a glycolytic phenotype. Here, we analyzed the expression of n = 67 genes involved in glycogen metabolism on the uveal melanoma (UM) cohort of the Cancer Genome Atlas (TCGA) study and validated the differentially expressed genes in an independent cohort. We also evaluated the glycogen levels with regard to the prognostic factors via a differential periodic acid-Schiff (PAS) staining. UMs with monosomy-3 exhibited a less glycogenetic and more insulin-resistant gene expression profile, together with the reduction of glycogen levels, which were associated with the metastases. Expression of glycogenin-1 (Locus: 3q24) was lower in the monosomy-3 tumors, whereas the complementary isoform glycogenin-2 (Locus: Xp22.33) was upregulated in females. Remarkably, glycogen was more abundant in the monosomy-3 tumors of male versus female patients. We therefore provide the first evidence to the dysregulation of glycogen metabolism as a novel factor that may be aggravating the course of UM particularly in males.
Novel Targeted Therapies for Metastatic Thyroid Cancer—A Comprehensive Review
Authors: Al-Jundi Mohammad , Thakur Shilpa , Gubbi Sriram , Klubo-Gwiezdzinska Joanna
Published: July 2020

The knowledge on thyroid cancer biology has grown over the past decade. Thus, diagnostic and therapeutic strategies to manage thyroid cancer are rapidly evolving. With new insights into tumor biology and cancer genetics, several novel therapies have been approved for the treatment of thyroid cancer. Tyrosine kinase inhibitors (TKIs), such as lenvatinib and sorafenib, have been successfully utilized for the treatment of radioactive iodine (RAI)-refractory metastatic differentiated thyroid cancer (DTC). In addition, pretreatment with mitogen-activated protein kinase (MAPK) inhibitors (trametinib and selumetinib) has been shown to restore RAI avidity in previously RAI-refractory DTCs. Local therapies, such as external beam radiation and radiofrequency/ethanol ablation, have also been employed for treatment of DTC. Vandetanib and cabozantinib are the two TKIs currently approved by the Food and Drug Administration (FDA) for the treatment of medullary thyroid cancer (MTC). Other novel therapies, such as peptide receptor radionuclide therapy and carcinoembryonic antigen (CEA) vaccine, have also been utilized in treating MTC. Ongoing trials on selective rearranged-during-transfection (RET) protooncogene inhibitors, such as LOXO-292 and BLU-667, have demonstrated promising results in the treatment of metastatic MTC resistant to non-selective TKIs. The FDA-approved BRAF/MEK inhibitor combination of dabrafenib and trametinib has revolutionized treatment of BRAFV600E mutation positive anaplastic thyroid cancer. Several other emerging classes of medications, such as gene fusion inhibitors and immune checkpoint inhibitors, are being actively investigated in several clinical trials. In this review, we describe the molecular landscape of thyroid cancer and novel targeted therapies and treatment combinations available for the treatment of metastatic thyroid cancer.
Role of MSC in the Tumor Microenvironment
Authors: Hass Ralf
Published: July 2020

The tumor microenvironment represents a dynamically composed matrix in which tissue-associated cancer cells are embedded together with a variety of further cell types to form a more or less separate organ-like structure. Constantly mutual interactions between cells of the tumor microenvironment promote continuous restructuring and growth in the tumor. A distinct organization of the tumor stroma also facilitates the formation of transient cancer stem cell niches, thereby contributing to progressive and dynamic tumor development. An important but heterogeneous mixture of cells that communicates among the cancer cells and the different tumor-associated cell types is represented by mesenchymal stroma-/stem-like cells (MSC). Following recruitment to tumor sites, MSC can change their functionalities, adapt to the tumor’s metabolism, undergo differentiation and synergize with cancer cells. Vice versa, cancer cells can alter therapeutic sensitivities and change metastatic behavior depending on the type and intensity of this MSC crosstalk. Thus, close cellular interactions between MSC and cancer cells can eventually promote cell fusion by forming new cancer hybrid cells. Consequently, newly acquired cancer cell functions or new hybrid cancer populations enlarge the plasticity of the tumor and counteract successful interventional strategies. The present review article highlights some important features of MSC within the tumor stroma.
Targeting Multiple Myeloma through the Biology of Long-Lived Plasma Cells
Authors: Utley Adam , Lipchick Brittany , Lee Kelvin P. , Nikiforov Mikhail A.
Published: July 2020

Multiple myeloma (MM) is a hematological malignancy of terminally differentiated bone marrow (BM) resident B lymphocytes known as plasma cells (PC). PC that reside in the bone marrow include a distinct population of long-lived plasma cells (LLPC) that have the capacity to live for very long periods of time (decades in the human population). LLPC biology is critical for understanding MM disease induction and progression because MM shares many of the same extrinsic and intrinsic survival programs as LLPC. Extrinsic survival signals required for LLPC survival include soluble factors and cellular partners in the bone marrow microenvironment. Intrinsic programs that enhance cellular fidelity are also required for LLPC survival including increased autophagy, metabolic fitness, the unfolded protein response (UPR), and enhanced responsiveness to endoplasmic reticulum (ER) stress. Targeting LLPC cell survival mechanisms have led to standard of care treatments for MM including proteasome inhibition (Bortezomib), steroids (Dexamethasone), and immunomodulatory drugs (Lenalidomide). MM patients that relapse often do so by circumventing LLPC survival pathways targeted by treatment. Understanding the mechanisms by which LLPC are able to survive can allow us insight into the treatment of MM, which allows for the enhancement of therapeutic strategies in MM both at diagnosis and upon patient relapse.
Intrinsic Radiosensitivity Is Not the Determining Factor in Treatment Response Differences between HPV Negative and HPV Positive Head and Neck Cancers
Authors: Reid Paul , Staudacher Alexander H. , Marcu Loredana G. , Olver Ian , Moghaddasi Leyla , Brown Michael P. , Li Yanrui , Bezak Eva
Published: July 2020

Head and neck squamous cell carcinomas (HNSCC) resulting from human papillomavirus (HPV) are increasing in incidence but demonstrate significantly better treatment response than HNSCC from other causes such as tobacco and alcohol. This study sought to identify differences in HNSCC, intrinsic to HPV status, in their response to radiation dose. Previously unexamined changes in radio-responsiveness following fractionated X-ray irradiation were compared between HPV positive and negative statuses of HNSCC. Six HNSCC cell lines, 3 of each HPV status, were investigated for radiosensitivity by clonogenic assay and modelled by response as a function of dose. Generational cultures of each cell line were developed to follow changes in radiosensitivity after repeated irradiations simulating fractionated radiation therapy. As a group, the HPV positive cell lines were more radiosensitive, but with changes following repeated fractions of dose, and modelling of response as a function of dose, both statuses displayed large radiobiological heterogeneity. These findings challenge current radiobiological assumptions of head and neck cancers as early responding tissue to radiation and may go some way in explaining difficulties reaching consensus in stratification of treatment by HPV status. Consequently, results from this study do not support stratifying radiation therapy by HPV status.
Evidence Supporting an Antimicrobial Origin of Targeting Peptides to Endosymbiotic Organelles
Authors: Garrido Clotilde , Caspari Oliver D. , Choquet Yves , Wollman Francis-André , Lafontaine Ingrid
Published: July 2020

Mitochondria and chloroplasts emerged from primary endosymbiosis. Most proteins of the endosymbiont were subsequently expressed in the nucleo-cytosol of the host and organelle-targeted via the acquisition of N-terminal presequences, whose evolutionary origin remains enigmatic. Using a quantitative assessment of their physico-chemical properties, we show that organelle targeting peptides, which are distinct from signal peptides targeting other subcellular compartments, group with a subset of antimicrobial peptides. We demonstrate that extant antimicrobial peptides target a fluorescent reporter to either the mitochondria or the chloroplast in the green alga Chlamydomonas reinhardtii and, conversely, that extant targeting peptides still display antimicrobial activity. Thus, we provide strong computational and functional evidence for an evolutionary link between organelle-targeting and antimicrobial peptides. Our results support the view that resistance of bacterial progenitors of organelles to the attack of host antimicrobial peptides has been instrumental in eukaryogenesis and in the emergence of photosynthetic eukaryotes.
Transcriptomic Profiling of Ca2+ Transport Systems during the Formation of the Cerebral Cortex in Mice
Authors: Bouron Alexandre
Published: July 2020

Cytosolic calcium (Ca2+) transients control key neural processes, including neurogenesis, migration, the polarization and growth of neurons, and the establishment and maintenance of synaptic connections. They are thus involved in the development and formation of the neural system. In this study, a publicly available whole transcriptome sequencing (RNA-Seq) dataset was used to examine the expression of genes coding for putative plasma membrane and organellar Ca2+-transporting proteins (channels, pumps, exchangers, and transporters) during the formation of the cerebral cortex in mice. Four ages were considered: embryonic days 11 (E11), 13 (E13), and 17 (E17), and post-natal day 1 (PN1). This transcriptomic profiling was also combined with live-cell Ca2+ imaging recordings to assess the presence of functional Ca2+ transport systems in E13 neurons. The most important Ca2+ routes of the cortical wall at the onset of corticogenesis (E11–E13) were TACAN, GluK5, nAChR β2, Cav3.1, Orai3, transient receptor potential cation channel subfamily M member 7 (TRPM7) non-mitochondrial Na+/Ca2+ exchanger 2 (NCX2), and the connexins CX43/CX45/CX37. Hence, transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1), transmembrane protein 165 (TMEM165), and Ca2+ “leak” channels are prominent intracellular Ca2+ pathways. The Ca2+ pumps sarco/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) and plasma membrane Ca2+ ATPase 1 (PMCA1) control the resting basal Ca2+ levels. At the end of neurogenesis (E17 and onward), a more numerous and diverse population of Ca2+ uptake systems was observed. In addition to the actors listed above, prominent Ca2+-conducting systems of the cortical wall emerged, including acid-sensing ion channel 1 (ASIC1), Orai2, P2X2, and GluN1. Altogether, this study provides a detailed view of the pattern of expression of the main actors participating in the import, export, and release of Ca2+. This work can serve as a framework for further functional and mechanistic studies on Ca2+ signaling during cerebral cortex formation.
iPS-Derived Early Oligodendrocyte Progenitor Cells from SPMS Patients Reveal Deficient In Vitro Cell Migration Stimulation
Authors: Lopez-Caraballo Lidia , Martorell-Marugan Jordi , Carmona-Sáez Pedro , Gonzalez-Munoz Elena
Published: July 2020

The most challenging aspect of secondary progressive multiple sclerosis (SPMS) is the lack of efficient regenerative response for remyelination, which is carried out by the endogenous population of adult oligoprogenitor cells (OPCs) after proper activation. OPCs must proliferate and migrate to the lesion and then differentiate into mature oligodendrocytes. To investigate the OPC cellular component in SPMS, we developed induced pluripotent stem cells (iPSCs) from SPMS-affected donors and age-matched controls (CT). We confirmed their efficient and similar OPC differentiation capacity, although we reported SPMS-OPCs were transcriptionally distinguishable from their CT counterparts. Analysis of OPC-generated conditioned media (CM) also evinced differences in protein secretion. We further confirmed SPMS-OPC CM presented a deficient capacity to stimulate OPC in vitro migration that can be compensated by exogenous addition of specific components. Our results provide an SPMS-OPC cellular model and encouraging venues to study potential cell communication deficiencies in the progressive form of multiple sclerosis (MS) for future treatment strategies.
The NLRP3 Inflammasome: Metabolic Regulation and Contribution to Inflammaging
Authors: Meyers Allison K. , Zhu Xuewei
Published: July 2020

In response to inflammatory stimuli, immune cells reconfigure their metabolism and bioenergetics to generate energy and substrates for cell survival and to launch immune effector functions. As a critical component of the innate immune system, the nucleotide-binding and oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome can be activated by various endogenous and exogenous danger signals. Activation of this cytosolic multiprotein complex triggers the release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and initiates pyroptosis, an inflammatory form of programmed cell death. The NLRP3 inflammasome fuels both chronic and acute inflammatory conditions and is critical in the emergence of inflammaging. Recent advances have highlighted that various metabolic pathways converge as potent regulators of the NLRP3 inflammasome. This review focuses on our current understanding of the metabolic regulation of the NLRP3 inflammasome activation, and the contribution of the NLRP3 inflammasome to inflammaging.