bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary Tryptophan Levels Impact Growth Performance and Intestinal Microbial Ecology in Weaned Piglets via Tryptophan Metabolites and Intestinal Antimicrobial Peptides
Authors: Rao Zebin , Li Jinlong , Shi Baoshi , Zeng Yan , Liu Yubo , Sun Zhihong , Wu Liuting , Sun Weizhong , Tang Zhiru
Published: March 2021

Tryptophan (Trp) plays an important role in piglet growth. However, the effect of dietary Trp on microbial flora is still poorly understood. A total of 40 28-d weaned piglets were allocated to four groups with 10 barrows per group and one pig per replicate. Piglets were fed a corn and soybean meal-based diet with 0.14%, 0.21%, 0.28%, or 0.35% Trp for four weeks. Five piglets from each diet group were euthanized, and blood and tissue samples were collected. The average daily body weight gain, average daily feed intake, feed conversion ratio, spleen index, pancreas index, longissimus dorsi muscle index, plasma insulin, 5-hydroxytryptamine, kynurenine, and Trp concentrations of weaned piglets increased in a dose-dependent manner (p < 0.05). Compared with the 0.14% Trp diet, the adequate-Trp diets (0.21%, 0.28%, or 0.35%) down-regulated the relative abundances of 12 genera including Turicibacter, Prevotella, Mitsuokella, Anaerovibrio, Megasphaera, Succinivibrio, Sutterella, Desulfovibrio, and Methanobrevibacter (p < 0.05); up-regulated the abundances of Ruminococcaceae, Lactobacillus, and Muribaculaceae in the colon (p < 0.05); and augmented the mRNA level and concentration of porcine β-defensin 2 in the small intestinal mucosa (p < 0.05). Moreover, Trp-adequate diets increased the abundances of Trp hydroxylase, indoleamine 2,3-dioxygenase, porcine β-defensin 2, phosphorylated mammalian target of rapamycin, and phosphorylated protein kinase B in the small intestinal mucosa (p < 0.05). We noted that a corn and soybean meal-based diet with 0.35% Trp may be a nutritional strategy to improve growth performance, intestinal mucosal barrier integrity, and intestinal microbial ecology in weaned piglets.
Balanced Intense Exercise Training Induces Atrial Oxidative Stress Counterbalanced by the Antioxidant System and Atrial Hypertrophy That Is Not Associated with Pathological Remodeling or Arrhythmogenicity
Authors: Oláh Attila , Barta Bálint András , Sayour Alex Ali , Ruppert Mihály , Virág-Tulassay Eszter , Novák Julianna , Varga Zoltán V. , Ferdinandy Péter , Merkely Béla , Radovits Tamás
Published: March 2021

Although regular exercise training is associated with cardiovascular benefits, the increased risk of atrial arrhythmias has been observed after vigorous exercise and has been related to oxidative stress. We aimed at investigating exercise-induced atrial remodeling in a rat model of an athlete’s heart and determining sex-specific differences. Age-matched young adult rats were divided into female exercised, female control, male exercised, and male control groups. After exercised animals completed a 12-week-long swim training protocol, echocardiography and in vivo cardiac electrophysiologic investigation were performed. Additionally, atrial histological and gene expression analyses were carried out. Post-mortem atrial weight data and histological examination confirmed marked atrial hypertrophy. We found increased atrial gene expression of antioxidant enzymes along with increased nitro-oxidative stress. No gene expression alteration was found regarding markers of pathological remodeling, apoptotic, proinflammatoric, and profibrotic processes. Exercise training was associated with a prolonged right atrial effective refractory period. We could not induce arrhythmias by programmed stimulation in any groups. We found decreased expression of potassium channels. Female gender was associated with lower profibrotic expression and collagen density. Long-term, balanced exercise training-induced atrial hypertrophy is not associated with harmful electrical remodeling, and no inflammatory or profibrotic response was observed in the atrium of exercised rats.
CTLA-2 Alpha Is a Potent Inhibitor of Angiogenesis in Murine Ocular Tissue
Authors: Maruyama Kazuichi , Yoneda Kazuhito , Sugita Sunao , Yamamoto Yoshimi , Koike Masato , Peters Christoph , Uchiyama Yasuo , Nishida Kohji
Published: March 2021

Cytotoxic T lymphocyte antigen-2 (CTLA-2) alpha has been reported to suppress the activities of cathepsin L (Cath L), which is deeply involved in angiogenesis. Therefore, we assessed whether CTLA-2 alpha plays a role in angiogenesis in ocular tissue. To establish models of corneal inflammation and experimental choroidal neovascularization (CNV), male C57BL/6J mice (n = 5) underwent corneal suture placement or laser-induced CNV, respectively. Mice were then injected with recombinant CTLA-2 alpha (1 µg) into the peritoneal cavity at day 0 and every 2 days after operation. In vitro experiments were performed to assess the inflammatory response by measuring TNF-alpha secretion in peritoneal cavity exudate cells (PECs) or the proliferation of mouse vascular endothelial cells (mVECs). CTLA-2 alpha treatment dramatically suppressed corneal angiogenesis, as well as laser-induced CNV. Moreover, CTLA-2 alpha inhibited the proliferation of mVECs in vitro, while CTLA-2 alpha abolishment was able to rescue proliferation. However, CTLA-2 alpha could not suppress cytokine secretion from inflammatory cells such as PECs. In summary, CTLA-2 alpha was able to suppress angiogenesis by suppressing endothelial cell proliferation. Further studies are needed to investigate its usefulness as a new antiangiogenic treatment for a variety of conditions, including age-related macular degeneration.
An Optimization Workflow in Design for Additive Manufacturing
Authors: Rosso Stefano , Uriati Federico , Grigolato Luca , Meneghello Roberto , Concheri Gianmaria , Savio Gianpaolo
Published: March 2021

Additive Manufacturing (AM) brought a revolution in parts design and production. It enables the possibility to obtain objects with complex geometries and to exploit structural optimization algorithms. Nevertheless, AM is far from being a mature technology and advances are still needed from different perspectives. Among these, the literature highlights the need of improving the frameworks that describe the design process and taking full advantage of the possibilities offered by AM. This work aims to propose a workflow for AM guiding the designer during the embodiment design phase, from the engineering requirements to the production of the final part. The main aspects are the optimization of the dimensions and the topology of the parts, to take into consideration functional and manufacturing requirements, and to validate the geometric model by computer-aided engineering software. Moreover, a case study dealing with the redesign of a piston rod is presented, in which the proposed workflow is adopted. Results show the effectiveness of the workflow when applied to cases in which structural optimization could bring an advantage in the design of a part and the pros and cons of the choices made during the design phases were highlighted.
Failure Mechanism of Back-Break in Bench Blasting of Thin Terrane
Authors: Wei Dong , Chen Ming , Lu Wenbo , Wang Zhihua
Published: March 2021

The shape of a free surface is an important factor that determines the effect of bench blasting. The structural dynamics theory was applied to establish a structural failure model of the layered rock considering the impact of a blasting gas intrusion. Combined with the continuous-discontinuous element method (CDEM), the influence of rock strata on the failure mechanism of back-break was analyzed. The results show that structural failure characteristics of stratum with different dip angles are different. The bending failure characteristics of dipping-in-face stratum are stronger than that in dipping-out-of-face stratum. With the increase of the dip angle and height of rock stratum, the bending failure length of dipping-in-face stratum increases and the maximum value reaches 5.24 m. The trend of failure along the stratum surface towards the bottom increases, which is an important reason for the formation of an unfavorable shape of free surface. However, the failure depth of the gently dipping stratum and dipping-out-of-face stratum is relatively uniform; the average value is about 0.5 m. Finally, combined with the results of the bench blasting field test of the Changjiu (Shenshan) limestone mine, which is the largest in the production of sand and gravel aggregates, we verify the correctness of the theoretical analysis results. Relevant research results can provide a theoretical basis and technical support for controlling the bench blasting effect.
Evaluation of Accuracy of Traffic Flow Generation in SUMO
Authors: Ma Xiaoyi , Hu Xiaowei , Weber Thomas , Schramm Dieter
Published: March 2021

A traffic simulation of the Jianghan Zone in Wuhan, China was carried out. In order to simulate genuine traffic flow without traditional hard-to-implement data collection methods, geographic population distribution data were gathered from the public information and traffic flow was generated by ActivityGen in SUMO (Simulation of Urban Mobility). For the sake of discovering the accuracy of the simulated traffic, real-time road condition and traffic prediction based on previous data on same time of each road in this area was compared. The results show that traffic flow generated from geographic population distribution data has referential meanings and with more detailed model classification, simulated traffic data can be closer to real conditions. This may offer a new way to generate traffic flow for researchers working in traffic simulation area. Further improvement of the accuracy in traffic flow generation by geographic population needs to pay more attention on special places like hospital and train stations.
Deep Reinforcement Learning-Based Path Planning for Multi-Arm Manipulators with Periodically Moving Obstacles
Authors: Prianto Evan , Park Jae-Han , Bae Ji-Hun , Kim Jung-Su
Published: March 2021

In the workspace of robot manipulators in practice, it is common that there are both static and periodic moving obstacles. Existing results in the literature have been focusing mainly on the static obstacles. This paper is concerned with multi-arm manipulators with periodically moving obstacles. Due to the high-dimensional property and the moving obstacles, existing results suffer from finding the optimal path for given arbitrary starting and goal points. To solve the path planning problem, this paper presents a SAC-based (Soft actor–critic) path planning algorithm for multi-arm manipulators with periodically moving obstacles. In particular, the deep neural networks in the SAC are designed such that they utilize the position information of the moving obstacles over the past finite time horizon. In addition, the hindsight experience replay (HER) technique is employed to use the training data efficiently. In order to show the performance of the proposed SAC-based path planning, both simulation and experiment results using open manipulators are given.
Bone Temperature Variation Using a 3D-Printed Surgical Guide with Internal Irrigation
Authors: Stocchero Michele , Sivolella Stefano , Brunello Giulia , Zoppello Arianna , Cavallin Francesco , Biasetto Lisa
Published: March 2021

Bone overheating is a possible cause of implants early failure. When a surgical guide is used, the risk of heat injury is greater due to the reduced efficacy of the irrigation. The aim of this ex vivo study was to evaluate the effect of an additional built-in irrigation on bone temperature variation during implant osteotomy. Twelve bovine ribs were used. Cone beam computerized tomography (CBCT) was performed and a 3D-printed surgical guide with additional built-in irrigation tubes was produced for each rib. A total of 48 osteotomies were prepared, to compare the supplementary internal irrigation system (Group A) with external irrigation alone (Group B), no irrigation (Group C) and with free-hand surgery with external irrigation (Group D). Temperature was measured by three thermocouples placed at depths of 1.5, 7, and 12 mm. The largest temperature variation at each thermocouple showed median values of 3.0 °C, 1.9 °C, and 2.3 °C in Group 1; 2.3 °C, 1.7 °C, and 0.9 °C in Group 2; 3.2 °C, 1.6 °C, and 2.0 °C in Group 3; 2.0 °C, 2.0 °C, and 1.3 °C in Group 4, respectively. No differences were found among the four groups. In general, the highest temperature increase was observed with the use of the first drill (cortical perforator). Post-experimental CBCT revealed the presence of radiopaque material clogging the aperture of the internal irrigation channels. Additional internal irrigation was not found to significantly contribute to decrease bone temperature in this ex vivo setting.
Evaluation of the Seismic Capacity of Existing Moment Resisting Frames by a Simplified Approach: Examples and Numerical Application
Authors: Montuori Rosario , Nastri Elide , Piluso Vincenzo , Todisco Paolo
Published: March 2021

The capacity of a structure can be assessed using inelastic analysis, requiring sophisticated numerical procedures such as pushover and incremental dynamic analyses. A simplified method for the evaluation of the seismic performance of steel moment resisting frames (MRFs) to be used in everyday practice has been recently proposed. This method evaluates the capacity of buildings employing an analytical trilinear model without resorting to any non−linear analysis. Despite the methodologies suggested by codes, the assessing procedure herein described is of easy application, also by hand calculation. Furthermore, it constitutes a suitable tool to check the capacity of the buildings designed with the new seismic code prescriptions. The proposed methodology has been set up through a large parametric analysis, carried out on 420frames designed according to three different approaches: the theory of plastic mechanism control (TPMC), ensuring the design of structures showing global collapse mechanism (GMRFs), the one based on the Eurocode 8 design requirements (SMRFs), and a simple design against horizontal loads (OMRFs) without specific seismic requirements. In this paper, some examples of the application of this simplified methodology are proposed with references to structures supposed to exhibit global, partial and soft storey mechanism.
Increasing the Reliability of an Electrical Power System in a Big European Hospital through the Petri Nets and Fuzzy Inference System Mamdani Modelling
Authors: Pinto Constâncio António , Farinha José Torres , Singh Sarbjeet , Raposo Hugo
Published: March 2021

The big hospitals’ electricity supply system’s reliability is discussed in this article through Petri nets and Fuzzy Inference System (FIS). To simulate and analyse an electric power system, the FIS Mamdani in MATLAB is implemented. The advantage of FIS is that it uses human experience to provide a faster solution than conventional techniques. The elements involved are the Main Electrical Power, the Generator sets, the Automatic Transfer Switches (ATS), and the Uninterrupted Power Supply (UPS), which are analysed to characterize the system behaviour. To evaluate the system and identified the lower reliability modules being proposed, a new reliable design model through the Petri Nets and Fuzzy Inference System approach. The resulting approach contributes to increasing the reliability of complex electrical systems, aiming to reduce their faults and increase their availability.
Exploring the Relationship between Internal Information Security, Response Cost, and Security Intention in Container Shipping
Authors: Wang Hsin-Wei , Kuo Szu-Yu , Chen Liang-Bi
Published: March 2021

This study empirically investigates the influence of information security marketing and response cost on employees’ information security intention in the container shipping industry. Survey data were collected from 285 respondents in Taiwan. Exploratory factor analysis was employed to identify all the measures to be summarized in a relative set. Confirmatory factor analysis was utilized to ensure every measure’s construct’s convergent and discriminant validity. Structural equation modeling was carried out to the proposed model in this article. The results indicate that organizational information security marketing has a positive impact on information security intention. Furthermore, this study conducted hierarchical regression to examine the moderating effects of information security awareness and information security climate. In particular, information security awareness significantly influenced the relationships between organizational information security marketing, response cost, and information security intention. Moreover, information security climate moderated the relationship between response cost and information security intention. This article concludes by discussing these theoretical and practical findings and implications.
Validation of Ensemble-Based Probabilistic Tropical Cyclone Intensity Change
Authors: Torn Ryan D. , DeMaria Mark
Published: March 2021

Although there has been substantial improvement to numerical weather prediction models, accurate predictions of tropical cyclone rapid intensification (RI) remain elusive. The processes that govern RI, such as convection, may be inherently less predictable; therefore a probabilistic approach should be adopted. Although there have been numerous studies that have evaluated probabilistic intensity (i.e., maximum wind speed) forecasts from high resolution models, or statistical RI predictions, there has not been a comprehensive analysis of high-resolution ensemble predictions of various intensity change thresholds. Here, ensemble-based probabilities of various intensity changes are computed from experimental Hurricane Weather Research and Forecasting (HWRF) and Hurricanes in a Multi-scale Ocean-coupled Non-hydrostatic (HMON) models that were run for select cases during the 2017–2019 seasons and verified against best track data. Both the HWRF and HMON ensemble systems simulate intensity changes consistent with RI (30 knots 24 h−1; 15.4 m s−1 24 h−1) less frequent than observed, do not provide reliable probabilistic predictions, and are less skillful probabilistic forecasts relative to the Statistical Hurricane Intensity Prediction System Rapid Intensification Index (SHIPS-RII) and Deterministic to Probabilistic Statistical (DTOPS) statistical-dynamical systems. This issue is partly alleviated by applying a quantile-based bias correction scheme that preferentially adjusts the model-based intensity change at the upper-end of intensity changes. While such an approach works well for high-resolution models, this bias correction strategy does not substantially improve ECMWF ensemble-based probabilistic predictions. By contrast, both the HWRF and HMON systems provide generally reliable predictions of intensity changes for cases where RI does not take place. Combining the members from the HWRF and HMON ensemble systems into a large multi-model ensemble does not improve upon HMON probablistic forecasts.
In Situ, Rotor-Based Drone Measurement of Wind Vector and Aerosol Concentration in Volcanic Areas
Authors: Sasaki Kansuke , Inoue Minoru , Shimura Tomoya , Iguchi Masato
Published: March 2021

Unmanned aerial vehicles (UAVs), represented by rotor-based drones, are suitable for volcanic observations owing to the advantages of mobility and safety. In this study, vertical profiles of wind and aerosol concentrations at altitudes up to 1000 m around Mt. Sakurajima, one of the most active volcanoes in Japan, were measured in situ using a drone equipped with an ultrasonic anemometer and aerosol sensor. The drone-measured wind profiles were compared with Doppler LiDAR data and analysis values derived from a meteorological model. Drone-measured vertical profiles collected at a vertical speed of 1 m·s−1 (upward and downward) showed strong agreement with the LiDAR observations, as did the averaged values of hovering drone measurements. Obvious vertical wind shear was found by the drone in the vicinity of Mt. Sakurajima. An aerosol sensor was installed on the drone with the capability to measure fine (PM2.5) and coarse particles (PM10) simultaneously; in this manner, volcanic ash and aerosol pollutants around the volcano could be distinguished. Thus, it was proven that drones could be applied to investigate wind conditions and aerosols in situ, even at dangerous locations near active volcanoes.
Green Roof Enhancement on Buildings of the University of Applied Sciences in Neubrandenburg (Germany) in Times of Climate Change
Authors: Köhler Manfred , Kaiser Daniel
Published: March 2021

The reduction in evaporative surfaces in cities is one driver for longer and hotter summers. Greening building surfaces can help to mitigate the loss of vegetated cover. Typical extensive green roof structures, such as sedum-based solutions, survive in dry periods, but how can green roofs be made to be more effective for the longer hot and dry periods to come? The research findings are based on continuous vegetation analytics of typical extensive green roofs over the past 20 years. -Survival of longer dry periods by fully adapted plants species with a focus on the fittest and best adapted species. -Additional technical and treatment solutions to support greater water storage in the media in dry periods and to support greater plant biomass/high biodiversity on the roofs by optimizing growing media with fertilizer to achieve higher evapotranspiration (short: ET) values. The main findings of this research: -The climate benefits of green roofs are associated with the quantity of phytomass. Selecting the right growing media is critical. -Typical extensive green roof substrates have poor nutrition levels. Fertilizer can significantly boost the ecological effects on CO2 fixation. -If the goal of the green roof is a highly biodiverse green roof, micro-structures are the right solution.
Outsourcing Reverse Logistics for E-Commerce Retailers: A Two-Stage Fuzzy Optimization Approach
Authors: Wang Chia-Nan , Dang Thanh-Tuan , Nguyen Ngoc-Ai-Thy
Published: March 2021

On the heels of the online shopping boom during the Covid-19 pandemic, the electronic commerce (e-commerce) surge has many businesses facing an influx in product returns. Thus, relevant companies must implement robust reverse logistics strategies to reflect the increased importance of the capability. Reverse logistics also plays a radical role in any business’s sustainable development as a process of reusing, remanufacturing, and redistributing products. Within this context, outsourcing to a third-party reverse logistics provider (3PRLP) has been identified as one of the most important management strategies for today’s organizations, especially e-commerce players. The objective of this study is to develop a decision support system to assist businesses in the selection and evaluation of different 3PRLPs by a hybrid fuzzy multicriteria decision-making (MCDM) approach. Relevant criteria concerning the economic, environmental, social, and risk factors are incorporated and taken into the models. For obtaining more scientific and accurate ranking results, linguistic terms are adopted to reduce fuzziness and uncertainties of criteria weights in the natural decision-making process. The fuzzy analytic hierarchy process (FAHP) is applied to measure the criteria’s relative significance over the evaluation process. The fuzzy technique for order preference by similarity to an ideal solution (FTOPSIS) is then used to rank the alternatives. The prescribed method was adopted for solving a case study on the 3PRLP selection for an online merchant in Vietnam. As a result, the most compatible 3PRLP was determined. The study also indicated that “lead time,” “customer’s voice,” “cost,” “delivery and service,” and “quality” are the most dominant drivers when selecting 3PLRLs. This study aims to provide a more complete and robust evaluation process to e-commerce businesses and any organization that deals with supply chain management in determining the optimized reverse logistics partners.
ParlTech: Transformation Framework for the Digital Parliament
Authors: Koryzis Dimitris , Dalas Apostolos , Spiliotopoulos Dimitris , Fitsilis Fotios
Published: March 2021

Societies are entering the age of technological disruption, which also impacts governance institutions such as parliamentary organizations. Thus, parliaments need to adjust swiftly by incorporating innovative methods into their organizational culture and novel technologies into their working procedures. Inter-Parliamentary Union World e-Parliament Reports capture digital transformation trends towards open data production, standardized and knowledge-driven business processes, and the implementation of inclusive and participatory schemes. Nevertheless, there is still a limited consensus on how these trends will materialize into specific tools, products, and services, with added value for parliamentary and societal stakeholders. This article outlines the rapid evolution of the digital parliament from the user perspective. In doing so, it describes a transformational framework based on the evaluation of empirical data by an expert survey of parliamentarians and parliamentary administrators. Basic sets of tools and technologies that are perceived as vital for future parliamentary use by intra-parliamentary stakeholders, such as systems and processes for information and knowledge sharing, are analyzed. Moreover, boundary conditions for development and implementation of parliamentary technologies are set and highlighted. Concluding recommendations regarding the expected investments, interdisciplinary research, and cross-sector collaboration within the defined framework are presented.
Milk Yield and Composition of Mixed-Breed Goats on Rangeland during the Dry Season and the Effect on the Growth of Their Progeny
Authors: Flores-Najera Manuel J. , Cuevas-Reyes Venancio , Vázquez-García Juan M. , Beltrán-López Sergio , Meza-Herrera César A. , Mellado Miguel , Negrete-Sánchez Luis O. , Rivas-Jacobo Marco A. , Rosales-Nieto Cesar A.
Published: March 2021

We tested whether the milk yield capacity of mixed-breed goats on a Chihuahuan desert rangeland in northern Mexico during the dry season affects milk composition, body weight gain, and weaning weight of their progeny. Milk yield and composition, and progeny postnatal growth performance, were recorded weekly. One week after kidding, mixed-breed goats (a mixture of Criollo × dairy breeds; n = 40) were allotted into medium (MP) or low (LP) milk yielding groups (20 goats per group). Mean 105-d total milk yield for MP and LP goats was 45.2 ± 12.5 and 20.7 ± 5.2 L, respectively. Milk lactose (4.3 vs. 4.2%) and solids-non-fat (SNF; 8.2 vs. 8.0) differed (p < 0.05) between MP and LP goats; milk protein content tended to differ (p = 0.08) between MP and LP goats with no difference for milk fat content (p > 0.05). Maternal body weight was positively associated with milk yield, milk lactose, and SNF content (p < 0.05 to p < 0.001). Goats giving birth to males produce more milk than goats giving birth to females, but milk fat percentage was higher in goats bearing females (p < 0.001). Milk yield and composition throughout lactation did not influence body weight gain (47.8 vs. 48.7 g/day for kids from MP and LP goats) and weaning weight (6.7 vs. 6.7 kg from MP and LP goats) of the offspring (p > 0.05). Birth weight and weaning weight of the progeny were positively related to maternal body weight (p ≤ 0.05). The postnatal growth of the kids was reduced, extending the time to reach market weight. Nevertheless, non-supplemented mixed-breed goats reared on semi-arid rangeland of northern Mexico have the potential for moderate milk production. Therefore, due to the limited nutrients ingested by grazing goats during the dry season, a nutritional supplement is necessary to keep up milk production and adequate growth of kids.
Asparagopsis armata Exudate Cocktail: The Quest for the Mechanisms of Toxic Action of an Invasive Seaweed on Marine Invertebrates
Authors: Silva Carla O. , Simões Tiago , Félix Rafael , Soares Amadeu M.V.M. , Barata Carlos , Novais Sara C. , Lemos Marco F.L.
Published: March 2021

The seaweed Asparagopsis armata exhibits a strong invasive behavior, producing halogenated compounds with effective biological effects. This study addresses the biochemical responses to sublethal concentrations of A. armata exudate on the marine snail Gibbula umbilicalis whole body and the shrimp Palaemon elegans eyes and hepatopancreas. Antioxidant defenses superoxide dismutase (SOD) and glutathione-S-transferase (GST), oxidative damage endpoints lipid peroxidation (LPO) and DNA damage, the neuronal parameter acetylcholinesterase (AChE), and the fatty acid profile were evaluated. Results revealed different metabolic responses in both species. Despite previous studies indicating that the exudate affected G. umbilicalis’ survival and behavior, this does not seem to result from oxidative stress or neurotoxicity. For P. elegans, the inhibition of AChE and the decrease of antioxidant capacity is concomitant with the increase of LPO, suggesting neurotoxicity and oxidative stress as contributor mechanisms of toxicity for this species. Fatty acid profile changes were more pronounced for P. elegans with a general increase in polyunsaturated fatty acids (PUFAs) with the exudate exposure, which commonly means a defense mechanism protecting from membrane disruption. Nonetheless, the omega-3 PUFAs arachidonic acid (ARA) and docosapentaenoic acid (DPA) increased in both invertebrates, indicating a common regulation mechanism of inflammation and immunity responses.
The Phosphorylation Status of Drp1-Ser637 by PKA in Mitochondrial Fission Modulates Mitophagy via PINK1/Parkin to Exert Multipolar Spindles Assembly during Mitosis
Authors: Ko Huey-Jiun , Tsai Cheng-Yu , Chiou Shean-Jaw , Lai Yun-Ling , Wang Chi-Huei , Cheng Jiin-Tsuey , Chuang Tsung-Hsien , Huang Chi-Ying F. , Kwan Aij-Lie , Loh Joon-Khim , Hong Yi-Ren
Published: March 2021

Mitochondrial fission and fusion cycles are integrated with cell cycle progression. Here we first re-visited how mitochondrial ETC inhibition disturbed mitosis progression, resulting in multipolar spindles formation in HeLa cells. Inhibitors of ETC complex I (rotenone, ROT) and complex III (antimycin A, AA) decreased the phosphorylation of Plk1 T210 and Aurora A T288 in the mitotic phase (M-phase), especially ROT, affecting the dynamic phosphorylation status of fission protein dynamin-related protein 1 (Drp1) and the Ser637/Ser616 ratio. We then tested whether specific Drp1 inhibitors, Mdivi-1 or Dynasore, affected the dynamic phosphorylation status of Drp1. Similar to the effects of ROT and AA, our results showed that Mdivi-1 but not Dynasore influenced the dynamic phosphorylation status of Ser637 and Ser616 in Drp1, which converged with mitotic kinases (Cdk1, Plk1, Aurora A) and centrosome-associated proteins to significantly accelerate mitotic defects. Moreover, our data also indicated that evoking mito-Drp1-Ser637 by protein kinase A (PKA) rather than Drp1-Ser616 by Cdk1/Cyclin B resulted in mitochondrial fission via the PINK1/Parkin pathway to promote more efficient mitophagy and simultaneously caused multipolar spindles. Collectively, this study is the first to uncover that mito-Drp1-Ser637 by PKA, but not Drp1-Ser616, drives mitophagy to exert multipolar spindles formation during M-phase.
On the Search of a Silver Bullet for the Preparation of Bioinspired Molecular Electrets with Propensity to Transfer Holes at High Potentials
Authors: Derr James Bennett , Rybicka-Jasińska Katarzyna , Espinoza Eli Misael , Morales Maryann , Billones Mimi Karen , Clark John Anthony , Vullev Valentine Ivanov
Published: March 2021

Biological structure-function relationships offer incomparable paradigms for charge-transfer (CT) science and its implementation in solar-energy engineering, organic electronics, and photonics. Electrets are systems with co-directionally oriented electric dopes with immense importance for CT science, and bioinspired molecular electrets are polyamides of anthranilic-acid derivatives with designs originating from natural biomolecular motifs. This publication focuses on the synthesis of molecular electrets with ether substituents. As important as ether electret residues are for transferring holes under relatively high potentials, the synthesis of their precursors presents formidable challenges. Each residue in the molecular electrets is introduced as its 2-nitrobenzoic acid (NBA) derivative. Hence, robust and scalable synthesis of ether derivatives of NBA is essential for making such hole-transfer molecular electrets. Purdie-Irvine alkylation, using silver oxide, produces with 90% yield the esters of the NBA building block for iso-butyl ether electrets. It warrants additional ester hydrolysis for obtaining the desired NBA precursor. Conversely, Williamson etherification selectively produces the same free-acid ether derivative in one-pot reaction, but a 40% yield. The high yields of Purdie-Irvine alkylation and the selectivity of the Williamson etherification provide important guidelines for synthesizing building blocks for bioinspired molecular electrets and a wide range of other complex ether conjugates.
Upper and Lower Motor Neuron Degenerations Are Somatotopically Related and Temporally Ordered in the Sod1 Mouse Model of Amyotrophic Lateral Sclerosis
Authors: Marques Christine , Burg Thibaut , Scekic-Zahirovic Jelena , Fischer Mathieu , Rouaux Caroline
Published: March 2021

Amyotrophic lateral sclerosis (ALS) is a devastating and fatal neurodegenerative disease arising from the combined degeneration of upper motor neurons (UMN) in the motor cortex, and lower motor neurons (LMN) in the brainstem and spinal cord. This dual impairment raises two major questions: (i) are the degenerations of these two neuronal populations somatotopically related? and if yes (ii), where does neurodegeneration start? If studies carried out on ALS patients clearly demonstrated the somatotopic relationship between UMN and LMN degenerations, their temporal relationship remained an unanswered question. In the present study, we took advantage of the well-described Sod1G86R model of ALS to interrogate the somatotopic and temporal relationships between UMN and LMN degenerations in ALS. Using retrograde labelling from the cervical or lumbar spinal cord of Sod1G86R mice and controls to identify UMN, along with electrophysiology and histology to assess LMN degeneration, we applied rigorous sampling, counting, and statistical analyses, and show that UMN and LMN degenerations are somatotopically related and that UMN depletion precedes LMN degeneration. Together, the data indicate that UMN degeneration is a particularly early and thus relevant event in ALS, in accordance with a possible cortical origin of the disease, and emphasize the need to further elucidate the molecular mechanisms behind UMN degeneration, towards new therapeutic avenues.
Systematic Review and Meta-Analysis of Surgical Treatment for Isolated Local Recurrence of Pancreatic Cancer
Authors: Serafini Simone , Sperti Cosimo , Friziero Alberto , Brazzale Alessandra Rosalba , Buratin Alessia , Ponzoni Alberto , Moletta Lucia
Published: March 2021

Purpose: To perform a systematic review and meta-analysis on the outcome of surgical treatment for isolated local recurrence of pancreatic cancer. Methods: A systematic review and meta-analysis based on Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines was conducted in PubMed, Scopus, and Web of Science. Results: Six studies concerning 431 patients with recurrent pancreatic cancer met the inclusion criteria and were included in the analysis: 176 underwent redo surgery, and 255 received non-surgical treatments. Overall survival and post-recurrence survival were significantly longer in the re-resected group (ratio of means (ROM) 1.99; 95% confidence interval (CI), 1.54–2.56, I2 = 75.89%, p = 0.006, and ROM = 2.05; 95% CI, 1.48–2.83, I2 = 76.39%, p = 0.002, respectively) with a median overall survival benefit of 28.7 months (mean difference (MD) 28.7; 95% CI, 10.3–47.0, I2 = 89.27%, p < 0.001) and median survival benefit of 15.2 months after re-resection (MD 15.2; 95% CI, 8.6–21.8, I2 = 58.22%, p = 0.048). Conclusion: Resection of isolated pancreatic cancer recurrences is safe and feasible and may offer a survival benefit. Selection of patients and assessment of time and site of recurrence are mandatory.
Doxorubicin-Loaded Gold Nanoarchitectures as a Therapeutic Strategy against Diffuse Intrinsic Pontine Glioma
Authors: Ung Caitlin , Tsoli Maria , Liu Jie , Cassano Domenico , Pocoví-Martínez Salvador , Upton Dannielle H. , Ehteda Anahid , Mansfeld Friederike M. , Failes Timothy W. , Farfalla Annafranca , Katsinas Christopher , Kavallaris Maria , Arndt Greg M. , Vittorio Orazio , Cirillo Giuseppe , Voliani Valerio , Ziegler David S.
Published: March 2021

Diffuse Intrinsic Pontine Gliomas (DIPGs) are highly aggressive paediatric brain tumours. Currently, irradiation is the only standard treatment, but is palliative in nature and most patients die within 12 months of diagnosis. Novel therapeutic approaches are urgently needed for the treatment of this devastating disease. We have developed non-persistent gold nano-architectures (NAs) functionalised with human serum albumin (HSA) for the delivery of doxorubicin. Doxorubicin has been previously reported to be cytotoxic in DIPG cells. In this study, we have preclinically evaluated the cytotoxic efficacy of doxorubicin delivered through gold nanoarchitectures (NAs-HSA-Dox). We found that DIPG neurospheres were equally sensitive to doxorubicin and doxorubicin-loaded NAs. Colony formation assays demonstrated greater potency of NAs-HSA-Dox on colony formation compared to doxorubicin. Western blot analysis indicated increased apoptotic markers cleaved Parp, cleaved caspase 3 and phosphorylated H2AX in NAs-HSA-Dox treated DIPG neurospheres. Live cell content and confocal imaging demonstrated significantly higher uptake of NAs-HSA-Dox into DIPG neurospheres compared to doxorubicin alone. Despite the potency of the NAs in vitro, treatment of an orthotopic model of DIPG showed no antitumour effect. This disparate outcome may be due to the integrity of the blood-brain barrier and highlights the need to develop therapies to enhance penetration of drugs into DIPG.
Oncolytic Virus Therapy Alters the Secretome of Targeted Glioblastoma Cells
Authors: Godlewski Jakub , Farhath Mohamed , Ricklefs Franz L. , Passaro Carmela , Kiel Klaudia , Nakashima Hiroshi , Chiocca E. Antonio , Bronisz Agnieszka
Published: March 2021

Oncolytic virus (OV) therapy, which is being tested in clinical trials for glioblastoma, targets cancer cells, while triggering immune cells. Yet OV sensitivity varies from patient to patient. As OV therapy is regarded as an anti-tumor vaccine, by making OV-infected cancer cells secrete immunogenic proteins, linking these proteins to transcriptome would provide a measuring tool to predict their sensitivity. A set of six patient-derived glioblastoma cells treated ex-vivo with herpes simplex virus type 1 (HSV1) modeled a clinical setting of OV infection. The cellular transcriptome and secreted proteome (separated into extracellular vesicles (EV) and EV-depleted fractions) were analyzed by gene microarray and mass-spectroscopy, respectively. Data validation and in silico analysis measured and correlated the secretome content with the response to infection and patient survival. Glioblastoma cells reacted to the OV infection in a seemingly dissimilar fashion, but their transcriptomes changed in the same direction. Therefore, the upregulation of transcripts encoding for secreted proteins implies a common thread in the response of cancer cells to infection. Indeed, the OV-driven secretome is linked to the immune response. While these proteins have distinct membership in either EV or EV-depleted fractions, it is their co-secretion that augments the immune response and associates with favorable patient outcomes.
p300 Serine 89: A Critical Signaling Integrator and Its Effects on Intestinal Homeostasis and Repair
Authors: Lai Keane K. Y. , Hu Xiaohui , Chosa Keisuke , Nguyen Cu , Lin David P. , Lai Keith K. , Kato Nobuo , Higuchi Yusuke , Highlander Sarah K. , Melendez Elizabeth , Eriguchi Yoshihiro , Fueger Patrick T. , Ouellette Andre J. , Chimge Nyam-Osor , Ono Masaya , Kahn Michael
Published: March 2021

Differential usage of Kat3 coactivators, CBP and p300, by β-catenin is a fundamental regulatory mechanism in stem cell maintenance and initiation of differentiation and repair. Based upon our earlier pharmacologic studies, p300 serine 89 (S89) is critical for controlling differential coactivator usage by β-catenin via post-translational phosphorylation in stem/progenitor populations, and appears to be a target for a number of kinase cascades. To further investigate mechanisms of signal integration effected by this domain, we generated p300 S89A knock-in mice. We show that S89A mice are extremely sensitive to intestinal insult resulting in colitis, which is known to significantly increase the risk of developing colorectal cancer. We demonstrate cell intrinsic differences, and microbiome compositional differences and differential immune responses, in intestine of S89A versus wild type mice. Genomic and proteomic analyses reveal pathway differences, including lipid metabolism, oxidative stress response, mitochondrial function and oxidative phosphorylation. The diverse effects on fundamental processes including epithelial differentiation, metabolism, immune response and microbiome colonization, all brought about by a single amino acid modification S89A, highlights the critical role of this region in p300 as a signaling nexus and the rationale for conservation of this residue and surrounding region for hundreds of million years of vertebrate evolution.
Molecular Profiling of Docetaxel-Resistant Prostate Cancer Cells Identifies Multiple Mechanisms of Therapeutic Resistance
Authors: Lima Thiago S. , Iglesias-Gato Diego , Souza Luciano D. O. , Stenvang Jan , Lima Diego S. , Røder Martin A. , Brasso Klaus , Moreira José M. A.
Published: March 2021

Docetaxel—a taxane-based chemotherapeutic agent—was the first treatment to demonstrate significant improvements in overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, the response to docetaxel is generally short-lived, and relapse eventually occurs due to the development of resistance. To explore the mechanisms of acquired docetaxel resistance in prostate cancer (PCa) and set these in the context of androgen deprivation therapy, we established docetaxel-resistant PCa cell lines, derived from the androgen-dependent LNCaP cell line, and from the LNCaP lineage-derived androgen-independent C4-2B sub-line. We generated two docetaxel-resistant LNCaPR and C4-2BR sub-lines, with IC50 values 77- and 50-fold higher than those of the LNCaP and C4-2B parental cells, respectively. We performed gene expression analysis of the matched sub-lines and found several alterations that may confer docetaxel resistance. In addition to increased expression of ABCB1, an ATP-binding cassette (ABC) transporter, and a well-known gene associated with development of docetaxel resistance, we identified genes associated with androgen signaling, cell survival, and overexpression of ncRNAs. In conclusion, we identified multiple mechanisms that may be associated with the development of taxane drug resistance in PCa. Actioning these mechanisms could provide a potential approach to re-sensitization of docetaxel-resistant PCa cells to docetaxel treatment and thereby further add to the life-prolonging effects of this drug in men with mCRPC.
Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives
Authors: Hafezi Shirin , Rahmani Mohamed
Published: March 2021

The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the proapoptotic proteins, which can be divided into two groups: the effectors (BAX, BAK, and BOK) and the BH3-only proteins (BIM, BAD, NOXA, PUMA, BID, BIK, HRK). Notably, the BCL-2 antiapoptotic proteins are often overexpressed in malignant cells. While this offers survival advantages to malignant cells and strengthens their drug resistance capacity, it also offers opportunities for novel targeted therapies that selectively kill such cells. This review provides a comprehensive overview of the extensive preclinical and clinical studies targeting BCL-2 proteins with various BCL-2 proteins inhibitors with emphasis on venetoclax as a single agent, as well as in combination with other therapeutic agents. This review also discusses recent advances, challenges focusing on drug resistance, and future perspectives for effective targeting the Bcl-2 family of proteins in cancer.
Interactome Mapping of eIF3A in a Colon Cancer and an Immortalized Embryonic Cell Line Using Proximity-Dependent Biotin Identification
Authors: Vo Diep-Khanh , Engler Alexander , Stoimenovski Darko , Hartig Roland , Kaehne Thilo , Kalinski Thomas , Naumann Michael , Haybaeck Johannes , Nass Norbert
Published: March 2021

Translation initiation comprises complex interactions of eukaryotic initiation factor (eIF) subunits and the structural elements of the mRNAs. Translation initiation is a key process for building the cell’s proteome. It not only determines the total amount of protein synthesized but also controls the translation efficiency for individual transcripts, which is important for cancer or ageing. Thus, understanding protein interactions during translation initiation is one key that contributes to understanding how the eIF subunit composition influences translation or other pathways not yet attributed to eIFs. We applied the BioID technique to two rapidly dividing cell lines (the immortalized embryonic cell line HEK-293T and the colon carcinoma cell line HCT-166) in order to identify interacting proteins of eIF3A, a core subunit of the eukaryotic initiation factor 3 complex. We identified a total of 84 interacting proteins, with very few proteins being specific to one cell line. When protein biosynthesis was blocked by thapsigargin-induced endoplasmic reticulum (ER) stress, the interacting proteins were considerably smaller in number. In terms of gene ontology, although eIF3A interactors are mainly part of the translation machinery, protein folding and RNA binding were also found. Cells suffering from ER-stress show a few remaining interactors which are mainly ribosomal proteins or involved in RNA-binding.
Comparing the Safety and Efficacy of Microwave Ablation Using ThermosphereTM Technology versus Radiofrequency Ablation for Hepatocellular Carcinoma: A Propensity Score-Matched Analysis
Authors: Kuroda Hidekatsu , Nagasawa Tomoaki , Fujiwara Yudai , Sato Hiroki , Abe Tamami , Kooka Yohei , Endo Kei , Oikawa Takayoshi , Sawara Kei , Takikawa Yasuhiro
Published: March 2021

There is limited information regarding the oncological benefits of microwave ablation using ThermosphereTM technology for hepatocellular carcinoma. This study compared the overall survival and recurrence-free survival outcomes among patients with hepatocellular carcinoma after microwave ablation using ThermosphereTM technology and after radiofrequency ablation. Between December 2017 and August 2020, 410 patients with hepatocellular carcinoma (a single lesion that was ≤5 cm or ≤3 lesions that were ≤3 cm) underwent ablation at our institution. Propensity score matching identified 150 matched pairs of patients with well-balanced characteristics. The microwave ablation and radiofrequency ablation groups had similar overall survival rates at 1 year (99.3% vs. 98.2%) and at 2 years (88.4% vs. 87.5%) (p = 0.728), as well as similar recurrence-free survival rates at 1 year (81.1% vs. 76.2%) and at 2 years (60.5% vs. 62.1%) (p = 0.492). However, the microwave ablation group had a significantly lower mean number of total insertions (1.22 ± 0.49 vs. 1.59 ± 0.94; p < 0.0001). This retrospective study revealed no significant differences in the overall survival and recurrence-free survival outcomes after microwave ablation or radiofrequency ablation. However, we recommend microwave ablation for hepatocellular carcinoma tumors with a diameter of >2 cm based on the lower number of insertions.