bluuebunny/crossref_metadata_2025 huggingface dataset:
Driver Behavior Analysis via Two-Stream Deep Convolutional Neural Network
Authors: Chen Ju-Chin , Lee Chien-Yi , Huang Peng-Yu , Lin Cheng-Rong
Published: March 2020

According to the World Health Organization global status report on road safety, traffic accidents are the eighth leading cause of death in the world, and nearly one-fifth of the traffic accidents were cause by driver distractions. Inspired by the famous two-stream convolutional neural network (CNN) model, we propose a driver behavior analysis system using one spatial stream ConvNet to extract the spatial features and one temporal stream ConvNet to capture the driver’s motion information. Instead of using three-dimensional (3D) ConvNet, which would suffer from large parameters and the lack of a pre-trained model, two-dimensional (2D) ConvNet is used to construct the spatial and temporal ConvNet streams, and they were pre-trained by the large-scale ImageNet. In addition, in order to integrate different modalities, the feature-level fusion methodology was applied, and a fusion network was designed to integrate the spatial and temporal features for further classification. Moreover, a self-compiled dataset of 10 actions in the vehicle was established. According to the experimental results, the proposed system can increase the accuracy rate by nearly 30% compared to the two-stream CNN model with a score-level fusion.
DeepDCA: Novel Network-Based Detection of IoT Attacks Using Artificial Immune System
Authors: Aldhaheri Sahar , Alghazzawi Daniyal , Cheng Li , Alzahrani Bander , Al-Barakati Abdullah
Published: March 2020

Recently Internet of Things (IoT) attains tremendous popularity, although this promising technology leads to a variety of security obstacles. The conventional solutions do not suit the new dilemmas brought by the IoT ecosystem. Conversely, Artificial Immune Systems (AIS) is intelligent and adaptive systems mimic the human immune system which holds desirable properties for such a dynamic environment and provides an opportunity to improve IoT security. In this work, we develop a novel hybrid Deep Learning and Dendritic Cell Algorithm (DeepDCA) in the context of an Intrusion Detection System (IDS). The framework adopts Dendritic Cell Algorithm (DCA) and Self Normalizing Neural Network (SNN). The aim of this research is to classify IoT intrusion and minimize the false alarm generation. Also, automate and smooth the signal extraction phase which improves the classification performance. The proposed IDS selects the convenient set of features from the IoT-Bot dataset, performs signal categorization using the SNN then use the DCA for classification. The experimentation results show that DeepDCA performed well in detecting the IoT attacks with a high detection rate demonstrating over 98.73% accuracy and low false-positive rate. Also, we compared these results with State-of-the-art techniques, which showed that our model is capable of performing better classification tasks than SVM, NB, KNN, and MLP. We plan to carry out further experiments to verify the framework using a more challenging dataset and make further comparisons with other signal extraction approaches. Also, involve in real-time (online) attack detection.
Analysis of a Sound Signal for Quality Monitoring in Laser Microlap Welding
Authors: Kuo Bo-Si , Lu Ming-Chyuan
Published: March 2020

This study focused on correlation analysis between welding quality and sound-signal features collected during microlaser welding. The study provides promising features for developing a monitoring system that detects low joint strength caused by a gap between metal sheets after welding. To obtain sound signals for signal analysis and develop the monitoring system, experiments for laser microlap welding were conducted on a laser microwelding platform by installing a microelectromechanical system (MEMS) microphone away from the welding point, and an acoustic emission (AE) sensor on the fixture. The gap between two metal sheet layers was controlled using clamp force, a pressing bar, and the appropriate installation of a thin piece of paper between the metal sheets. After sound signals from the microphone were collected, the correlation between features of time-domain sound signals and of welding quality was analyzed by categorizing the referred signals into eight sections during welding. After appropriately generating the features after signal analysis and selecting the most promising features for low-joint-strength monitoring on the basis of scatter index J, a hidden Markov model (HMM)-based classifier was applied to evaluate the performance of the selected sound-signal features. Results revealed that three sound-signal features were closely related to joint-strength variation caused by the gap between two metal-sheet layers: (1) the root-mean-square (RMS) value of the first section of sound signals, (2) the standard deviation of the first section of sound signals, and (3) the standard deviation to the RMS ratio of the second section of sound signals. In system evaluation, a 100% classification rate was obtained for normal and low-bonding-strength monitoring when the HMM-based classifier was developed on the basis of the three selected features.
The Influence of the Load Term of the Strain Energy Sensitivity in the Shell Shape Optimization
Authors: Jiang Baoshi , Cui Changyu , Wang Jianghong
Published: March 2020

The sensitivity method is a type of effective shape optimization method and the strain energy is a frequently used objective function. The change of a surface shape inevitably causes a change in its quality. However, the influence of the load term on strain energy sensitivity has not been considered in many studies. In order to make the influence clear, the formula of the strain energy sensitivity including the load term was first derived. Secondly, the influence of the sensitivity load term on the structural evolution was studied by using different optimization schemes. The results showed that the load term of strain energy sensitivity accounts for a small proportion of the whole strain energy sensitivity, but it still has a cumulative impact on the structural evolution, and the shell thickness has an impact on the role of the load term of the strain energy sensitivity. The load term could influence the rate of increase in the structural weight and had an impact on the shape change to some extent. Therefore, for general construction projects, the strain energy sensitivity should be with the load term if the shell thickness is very thin or a higher performance of the structure is required.
Failure Analysis of SAC305 Ball Grid Array Solder Joint at Extremely Cryogenic Temperature
Authors: Li Yanruoyue , Fu Guicui , Wan Bo , Jiang Maogong , Zhang Weifang , Yan Xiaojun
Published: March 2020

To verify the reliability of a typical Pb-free circuit board applied for space exploration, five circuits were put into low temperature and shock test. However, after the test, memories on all five circuits were out of function. To investigate the cause of the failure, a series of methods for failure analysis was carried out, including X-ray detection, cross-section analysis, Scanning Electron Microscope (SEM) analysis, and contrast test. Through failure analysis, the failure was located in the Pb-free (Sn-3.0Ag-0.5Cu) solder joint, and we confirmed that the failure occurred because of the low temperature and change of fracture characteristic of Sn-3.0Ag-0.5Cu (SAC305). A verification test was conducted to verify the failure mechanism. Through analyzing data and fracture surface morphology, the cause of failure was ascertained. At low temperature, the fracture characteristic of SAC305 changed from ductileness to brittleness. The crack occurred at solder joints because of stress loaded by shock test. When the crack reached a specific length, the failure occurred. The temperature of the material’s characteristic change was −70–−80 °C. It could be a reference for Pb-free circuit board use in a space environment.
Evaluation of the Soil, Vegetation, and Snow (SVS) Land Surface Model for the Simulation of Surface Energy Fluxes and Soil Moisture under Snow-Free Conditions
Authors: Leonardini Gonzalo , Anctil François , Abrahamowicz Maria , Gaborit Étienne , Vionnet Vincent , Nadeau Daniel F. , Fortin Vincent
Published: March 2020

The recently developed Soil, Vegetation, and Snow (SVS) land surface model is being progressively implemented at Environment and Climate Change Canada (ECCC) for operational numerical weather and hydrological predictions. The objective of this study is to evaluate the ability of SVS, in offline point-scale mode and under snow-free conditions, to simulate the surface heat fluxes and soil moisture when compared to flux tower observations and simulations from the Canadian Land Surface Scheme (CLASS), used here as a benchmark model. To do this, we performed point-scale simulations of between 4 and 12 years of data records at six selected sites of the FLUXNET network under arid, Mediterranean and tropical climates. At all sites, SVS shows realistic simulations of latent heat flux, sensible heat flux and net radiation. Soil heat flux is reasonably well simulated for the arid sites and one Mediterranean site and poorly simulated for the tropical sites. On the other hand, surface soil moisture was reasonably well simulated at the arid and Mediterranean sites and poorly simulated at the tropical sites. SVS performance was comparable to CLASS not only for energy fluxes and soil moisture, but also for more specific processes such as evapotranspiration and water balance.
Overview of Injuries Associated with Extreme Weather Events in New Hampshire, U.S., 2001–2009
Authors: Neugent Kelly , Bush Kathleen F. , Kelsey Eric , Cahillane Matthew , Laflamme Eric
Published: March 2020

Global climate change is an environmental hazard with significant public health impacts. High-impact weather events including periods of extreme temperature or extreme precipitation are frequently associated with adverse effects on human health. This study evaluates the impact of extreme weather events on injuries across New Hampshire. A set of five daily extreme weather metrics (EWMs) was analyzed: daily maximum temperature ≤32 °F (0 °C), daily maximum temperature ≥90 °F (32 °C), daily maximum temperature ≥95 °F (35 °C), daily precipitation ≥1″, and daily precipitation ≥2″. Exposure to these EWMs was defined by linking the population within 10 miles of nine weather stations distributed across the state. Injuries were defined as hospitalizations categorized as: all-cause injury, vehicle accidents, accidental falls, accidents due to natural and environmental causes (including excessive heat, excessive cold, exposure due to weather conditions, lightning, and storms and floods), accidental drowning, and carbon monoxide poisoning. The associations between all injury categories and all EWMs as well as daily maximum temperature and daily precipitation were explored. A quasi-Poisson regression model was used to evaluate the relationship between the four strongest exposure–outcome pairs linking maximum temperature to all-cause injury-, vehicle accident-, accidental fall-, and heat-related hospital visits. Results indicate that daily maximum temperature (>90 °F) was most strongly associated with heat-related hospital visits and was also associated with all-cause injury-related hospital visits. Future work should include further analysis of cold weather metrics and incorporate these findings into public health planning and response efforts.
Post-Ischaemic Immunological Response in the Brain: Targeting Microglia in Ischaemic Stroke Therapy
Authors: Rawlinson Charlotte , Jenkins Stuart , Thei Laura , Dallas Mark L. , Chen Ruoli
Published: March 2020

Microglia, the major endogenous immune cells of the central nervous system, mediate critical degenerative and regenerative responses in ischaemic stroke. Microglia become “activated”, proliferating, and undergoing changes in morphology, gene and protein expression over days and weeks post-ischaemia, with deleterious and beneficial effects. Pro-inflammatory microglia (commonly referred to as M1) exacerbate secondary neuronal injury through the release of reactive oxygen species, cytokines and proteases. In contrast, microglia may facilitate neuronal recovery via tissue and vascular remodelling, through the secretion of anti-inflammatory cytokines and growth factors (a profile often termed M2). This M1/M2 nomenclature does not fully account for the microglial heterogeneity in the ischaemic brain, with some simultaneous expression of both M1 and M2 markers at the single-cell level. Understanding and regulating microglial activation status, reducing detrimental and promoting repair behaviours, present the potential for therapeutic intervention, and open a longer window of opportunity than offered by acute neuroprotective strategies. Pharmacological modulation of microglial activation status to promote anti-inflammatory gene expression can increase neurogenesis and improve functional recovery post-stroke, based on promising preclinical data. Cell-based therapies, using preconditioned microglia, are of interest as a method of therapeutic modulation of the post-ischaemic inflammatory response. Currently, there are no clinically-approved pharmacological options targeting post-ischaemic inflammation. A major developmental challenge for clinical translation will be the selective suppression of the deleterious effects of microglial activity after stroke whilst retaining (or enhancing) the neurovascular repair and remodelling responses of microglia.
Comparative Life Cycle Assessment of Steel and Concrete Construction Frames: A Case Study of Two Residential Buildings in Iran
Authors: Oladazimi Amir , Mansour Saeed , Hosseinijou Seyed
Published: March 2020

Given the fact that during the recent years the majority of buildings in Iran have been constructed either on steel or concrete frames, it is essential to investigate the environmental impacts of materials used in such constructions. For this purpose, two multi-story residential buildings in Tehran with a similar function have been considered in this study. One building was constructed with a steel frame and the other was constructed with a concrete frame. Using the life cycle assessment tool, a complete analysis of all the stages of a building’s life cycle from raw material acquisition to demolition and recycling of wastes was carried out. In this research, the environmental impacts included global warming potential in 100 years, acidification, eutrophication potential, human toxicity (cancer and non-cancer effects), resource depletion (water and mineral), climate change, fossil fuel consumption, air acidification and biotoxicity. It could be concluded from the results that the total pollution of the concrete frame in all eleven aforementioned impact factors was almost 219,000 tonnes higher than that of the steel frame. Moreover, based on the results, the concrete frame had poorer performance in all but one impact factor. With respect to global warming potential, the findings indicated there were two types of organic and non-organic gases that had an impact on global warming. Among non-organic emissions, CO2 had the biggest contribution to global warming potential, while among organic emissions, methane was the top contributor. These findings suggest the use of steel frames in the building industry in Iran to prevent further environmental damage; however, in the future, more research studies in this area are needed to completely investigate all aspects of decision on the choice of building frames, including economic and social aspects.
The Impacts of Air Leakage Paths and Airtightness Levels on Air Change Rates
Authors: Cardoso Vitor E. M. , Pereira Pedro F. , Ramos Nuno M. M. , Almeida Ricardo M. S. F.
Published: March 2020

Southern European countries have milder climatic conditions that differ from their colder northern counterparts, which greatly influence indoor ventilation strategies. The relation between a building’s airtightness and the air change rates remains a topic to be fully tackled in these countries, since natural ventilation is very frequent. In this work, the ventilation and airtightness of a case study were analyzed in-depth to support a discussion on this topic. CO2 concentration decay and blower-door measurements were used to characterize the infiltration and ventilation conditions of the case study. The case study represents a common Portuguese situation, with highly permeable envelopes, combined with highly variable air change rates. Transient simulations were carried out for the comparison of scenarios where different configurations of possible air paths were analyzed. The simulations included both natural and mechanical ventilation scenarios. An air sweeping effect from bedroom to bathroom only occurred when the mechanical extraction ventilation (MEV) was on. Different air leakage path configurations resulted in substantial offsets, up to 63%, of the air change rate (ACH) due to natural occurring forces. The results confirmed that the relation between airtightness and air change rates should be carefully analyzed in southern European countries, as indoor air quality, comfort of occupants, and energy efficiency are highly influenced by the considered variables.
The Interplay between Antiviral Signalling and Carcinogenesis in Human Papillomavirus Infections
Authors: Ferreira Ana Rita , Ramalho Ana Catarina , Marques Mariana , Ribeiro Daniela
Published: March 2020

Human papillomaviruses (HPV) are the causative agents of the most common sexually transmitted infection worldwide. While infection is generally asymptomatic and can be cleared by the host immune system, when persistence occurs, HPV can become a risk factor for malignant transformation. Progression to cancer is actually an unintended consequence of the complex HPV life cycle. Different antiviral defence mechanisms recognize HPV early in infection, leading to the activation of the innate immune response. However, the virus has evolved several specific strategies to efficiently evade the antiviral immune signalling. Here, we review and discuss the interplay between HPV and the host cell innate immunity. We further highlight the evasion strategies developed by different HPV to escape this cellular response and focus on the correlation with HPV-induced persistence and tumorigenesis.
Benefits of Combined All-Trans Retinoic Acid and Arsenic Trioxide Treatment of Acute Promyelocytic Leukemia Cells and Further Enhancement by Inhibition of Atypically Expressed Transglutaminase 2
Authors: Jambrovics Károly , Uray Iván P. , Keillor Jeffrey W. , Fésüs László , Balajthy Zoltán
Published: March 2020

Randomized trials in acute promyelocytic leukemia patients have shown that treatment with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) is superior in efficacy to monotherapy, with significantly decreased mortality. So far, there are little data available to explain the success of the ATRA and ATO combination treatment in molecular terms. We showed that ATRA- and ATO-treated cells had the same capacity for superoxide production, which was reduced by two-thirds in the combined treatment. Secreted inflammatory biomarkers (monocyte chemoattractant protein-1 [MCP-1], interleukin-1 beta [IL-1β] and tumor necrosis factor-α [TNF-α]) were significantly decreased and were further reduced in a transglutaminase 2 (TG2) expression-dependent manner. The amount of secreted TNF-α in the supernatant of NB4 TG2 knockout cells was close to 50 times lower than in ATRA-treated differentiated wild-type NB4 cells. The irreversible inhibitor of TG2 NC9 not only decreased reactive oxygen species production 28-fold, but decreased the concentration of MCP-1, IL-1β and TNF-α 8-, 15- and 61-fold, respectively in the combined ATRA + ATO-treated wild-type NB4 cell culture. We propose that atypical expression of TG2 leads to the generation of inflammation, which thereby serves as a potential target for the prevention of differentiation syndrome.
Human Cancer-Associated Mutations of SF3B1 Lead to a Splicing Modification of Its Own RNA
Authors: Bergot Tiffany , Lippert Eric , Douet-Guilbert Nathalie , Commet Séverine , Corcos Laurent , Bernard Delphine G.
Published: March 2020

Deregulation of pre-mRNA splicing is observed in many cancers and hematological malignancies. Genes encoding splicing factors are frequently mutated in myelodysplastic syndromes, in which SF3B1 mutations are the most frequent. SF3B1 is an essential component of the U2 small nuclear ribonucleoprotein particle that interacts with branch point sequences close to the 3’ splice site during pre-mRNA splicing. SF3B1 mutations mostly lead to substitutions at restricted sites in the highly conserved HEAT domain, causing a modification of its function. We found that SF3B1 was aberrantly spliced in various neoplasms carrying an SF3B1 mutation, by exploring publicly available RNA sequencing raw data. We aimed to characterize this novel SF3B1 transcript, which is expected to encode a protein with an insertion of eight amino acids in the H3 repeat of the HEAT domain. We investigated the splicing proficiency of this SF3B1 protein isoform, in association with the most frequent mutation (K700E), through functional complementation assays in two myeloid cell lines stably expressing distinct SF3B1 variants. The yeast Schizosaccharomyces pombe was also used as an alternative model. Insertion of these eight amino acids in wild-type or mutant SF3B1 (K700E) abolished SF3B1 essential function, highlighting the crucial role of the H3 repeat in the splicing function of SF3B1.
BNIP3L-Dependent Mitophagy Promotes HBx-Induced Cancer Stemness of Hepatocellular Carcinoma Cells via Glycolysis Metabolism Reprogramming
Authors: Chen Yuan-Yuan , Wang Wei-Hua , Che Lin , Lan You , Zhang Li-Yin , Zhan Deng-Lin , Huang Zi-Yan , Lin Zhong-Ning , Lin Yu-Chun
Published: March 2020

Hepatitis B virus (HBV) is one of predisposing factors for hepatocellular carcinoma (HCC). The role of HBV x protein (HBx) in mediating the induction and maintenance of cancer stemness during HBV-related HCC attracts considerable attention, but the exact mechanism has not been clearly elucidated. Here, ABCG2-dependent stem-like side population (SP) cells, which are thought to be liver cancer stem cells (LCSCs), were present in HCC cells, and the fraction of this subset was increased in HBx-expressing HCC cells. In addition, glycolysis was upregulated in LCSCs and HBx-expressing HCC cells, and intervention of glycolysis attenuated cancer stem-like phenotypes. Mitochondria play an important role in the maintenance of energy homeostasis, BNIP3L-dependent mitophagy was also activated in LCSCs and HBx-expressing HCC cells, which triggered a metabolic shift toward glycolysis. In summary, we proposed a positive feedback loop, in which HBx induced BNIP3L-dependent mitophagy which upregulated glycolytic metabolism, increasing cancer stemness of HCC cells in vivo and in vitro. BNIP3L might be a potential therapeutic target for intervention of LCSCs-associated HCC. Anti-HBx, a monoclonal antibody targeting intracellular HBx, had the potential to delay the progression of HBV infection related-HCC.
Safety and Effectiveness of Aflibercept + Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) for the Treatment of Patients with Metastatic Colorectal Cancer (mCRC) in Current Clinical Practice: OZONE Study
Authors: Chau Ian , Fakih Marwan , García-Alfonso Pilar , Linke Zdenĕk , Ruiz Casado Ana , Marques Eduardo Polo , Picard Pascaline , Celanovic Marina , Cartwright Thomas
Published: March 2020

For patients with metastatic colorectal cancer (mCRC) that have failed a first-line oxaliplatin-based regimen, the preferred treatment option is an irinotecan-based regimen. This prospective, observational, noncomparative, post-authorization safety study (OZONE) evaluated the safety and effectiveness of aflibercept plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) in patients with mCRC treated in daily practice after failure of an oxaliplatin-based regimen. Patients were grouped by age, renal impairment, hepatic impairment, race, number, and type of prior anticancer therapy. Of 766 treated patients enrolled, 59.5% were male, 94.8% had an Eastern Cooperative Oncology Group performance status of 0–1, all received previous chemotherapy (97.8% including oxaliplatin), and 58.6% had prior exposure to bevacizumab. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 68.3% of patients. Neutropenia, hypertension, diarrhea, and asthenia were the most frequently occurring grade ≥ 3 TEAEs. Antivascular endothelial growth factor class events were infrequent. Subgroup analyses did not reveal major differences in the safety profile according to age, renal and hepatic status, race, or prior anticancer therapy. For the total population, median overall survival was 12.5 months, median progression-free survival was 6.1 months, and overall response rate was 16.3%. Aflibercept in combination with FOLFIRI is a safe and efficacious regimen administered in current clinical practice to patients with mCRC previously treated with oxaliplatin. The study results, conducted in real-world clinical practice with a less selected patient population, are aligned with the VELOUR (NCT00561470) trial and no new safety issues were identified.
MR and CT Imaging of the Normal Eyelid and its Application in Eyelid Tumors
Authors: Ferreira Teresa A. , Pinheiro Carolina F. , Saraiva Paulo , Jaarsma-Coes Myriam G. , Van Duinen Sjoerd G. , Genders Stijn W. , Marinkovic Marina , Beenakker Jan-Willem M.
Published: March 2020

T-staging of most eyelid malignancies includes the assessment of the integrity of the tarsal plate and orbital septum, which are not clinically accessible. Given the contribution of MRI in the characterization of orbital tumors and establishing their relations to nearby structures, we assessed its value in identifying different eyelid structures in 38 normal eyelids and evaluating tumor extension in three cases of eyelid tumors. As not all patients can receive an MRI, we evaluated those same structures on CT and compared both results. All eyelid structures were identified on MRI and CT, except for the conjunctiva on both techniques and for the tarsal muscles on CT. Histopathology confirmed the MRI findings of orbital septum invasion in one patient, and the MRI findings of intact tarsus and orbital septum in another patient. Histopathology could not confirm or exclude tarsal invasion seen on MRI on two patients. Although imaging the eyelid is challenging, the identification of most eyelid structures is possible with MRI and, to a lesser extent, with CT and can, therefore, have an important contribution to the T-staging of eyelid tumors, which may improve treatment planning and outcome.
The Lipid Virulence Factors of Mycobacterium tuberculosis Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages
Authors: Bah Aïcha , Sanicas Merlin , Nigou Jérôme , Guilhot Christophe , Astarie-Dequeker Catherine , Vergne Isabelle
Published: March 2020

Autophagy is an important innate immune defense mechanism that controls Mycobacterium tuberculosis (Mtb) growth inside macrophages. Autophagy machinery targets Mtb-containing phagosomes via xenophagy after damage to the phagosomal membrane due to the Type VII secretion system Esx-1 or via LC3-associated phagocytosis without phagosomal damage. Conversely, Mtb restricts autophagy-related pathways via the production of various bacterial protein factors. Although bacterial lipids are known to play strategic functions in Mtb pathogenesis, their role in autophagy manipulation remains largely unexplored. Here, we report that the lipid virulence factors sulfoglycolipids (SLs) and phthiocerol dimycocerosates (DIMs) control autophagy-related pathways through distinct mechanisms in human macrophages. Using knock-out and knock-in mutants of Mtb and Mycobacterium bovis BCG (Bacille Calmette Guerin) and purified lipids, we found that (i) Mtb mutants with DIM and SL deficiencies promoted functional autophagy via an MyD88-dependent and phagosomal damage-independent pathway in human macrophages; (ii) SLs limited this pathway by acting as TLR2 antagonists; (iii) DIMs prevented phagosomal damage-independent autophagy while promoting Esx-1-dependent xenophagy; (iv) and DIMs, but not SLs, limited the acidification of LC3-positive Mtb compartments. In total, our study reveals an unexpected and intricate role for Mtb lipid virulence factors in controlling autophagy-related pathways in human macrophages, thus providing further insight into the autophagy manipulation tactics deployed by intracellular bacterial pathogens.
Oral Administration of Alpha Linoleic Acid Rescues Aβ-Induced Glia-Mediated Neuroinflammation and Cognitive Dysfunction in C57BL/6N Mice
Authors: Ali Waqar , Ikram Muhammad , Park Hyun Young , Jo Min Gi , Ullah Rahat , Ahmad Sareer , Abid Noman Bin , Kim Myeong Ok
Published: March 2020

In this work, we evaluated the effects of alpha linoleic acid (ALA), an omega-3 polyunsaturated fatty acid, on amyloid-beta-induced glial-cell-mediated neuroinflammation, amyloidogenesis, and cognitive dysfunction in mice. After an infusion of Aβ1–42 (Aβ1–42, 5 μL/5 min/mouse, intracerebroventricular injection (i.c.v), and respective treatments of ALA (60 mg/kg per oral for six weeks), neuroinflammation, apoptotic markers, and synaptic markers were evaluated by Western blot and immunofluorescence analyses. According to our findings, the infusion of Aβ1–42 activated Toll-like receptor 4 (TLR4), glial fibrillary acidic protein (GFAP), and ionized calcium adaptor molecule 1 (Iba-1) in the frontal cortices and hippocampi of the Aβ1–42-injected mice to a greater extent than the Aβ1–42 + ALA-cotreated mice. Similarly, there was an elevated expression of phospho-c-Jun-N-terminal kinase (p-JNK), phospho-nuclear factor-kB p65 (p-NF-kB p65 (Ser536)), and tissue necrosis factor (TNF) in the Aβ1–42 infused mouse brains; interestingly, these markers were significantly reduced in the Aβ + ALA-cotreated group. The elevated expression of pro-apoptotic markers was observed during apoptotic cell death in the Aβ1–42-treated mouse brains, whereas these markers were markedly reduced in the Aβ + ALA-cotreated group. Moreover, Aβ1–42 infusion significantly increased amyloidogenesis, as assessed by the enhanced expression of the amyloid precursor proteins (APP) beta-amyloid cleaving enzyme-1 (BACE-1) and amyloid-beta (Aβ1–42) in the mouse brains, whereas these proteins were markedly reduced in the Aβ + ALA-cotreated group. We also checked the effects of ALA against Aβ-triggered synaptic dysfunction and memory dysfunction, showing that ALA significantly improved memory and synaptic functions in Aβ-treated mouse brains. These results indicated that ALA could be an applicable intervention in neuroinflammation, apoptotic cell loss, amyloidogenesis, and memory dysfunction via the inhibition of TLR4 and its downstream targets in Aβ + ALA-cotreated mouse brains.
Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases
Authors: Song Ping , An Junqing , Zou Ming-Hui
Published: March 2020

Senescent cells are generally characterized by permanent cell cycle arrest, metabolic alteration and activation, and apoptotic resistance in multiple organs due to various stressors. Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ ageing. Immune cells can remove senescent cells. Immunaging or impaired innate and adaptive immune responses by senescent cells result in persistent accumulation of various senescent cells. Although senolytics—drugs that selectively remove senescent cells by inducing their apoptosis—are recent hot topics and are making significant research progress, senescence immunotherapies using immune cell-mediated clearance of senescent cells are emerging and promising strategies to fight ageing and multiple chronic diseases. This short review provides an overview of the research progress to date concerning senescent cell-caused chronic diseases and tissue ageing, as well as the regulation of senescence by small-molecule drugs in clinical trials and different roles and regulation of immune cells in the elimination of senescent cells. Mounting evidence indicates that immunotherapy targeting senescent cells combats ageing and chronic diseases and subsequently extends the healthy lifespan.
Cyclin-Dependent Kinase 18 Controls Trafficking of Aquaporin-2 and Its Abundance through Ubiquitin Ligase STUB1, Which Functions as an AKAP
Authors: Dema Alessandro , Faust Dörte , Lazarow Katina , Wippich Marc , Neuenschwander Martin , Zühlke Kerstin , Geelhaar Andrea , Pallien Tamara , Hallscheidt Eileen , Eichhorst Jenny , Wiesner Burkhard , Černecká Hana , Popp Oliver , Mertins Philipp , Dittmar Gunnar , von Kries Jens Peter , Klussmann Enno
Published: March 2020

Arginine-vasopressin (AVP) facilitates water reabsorption in renal collecting duct principal cells through regulation of the water channel aquaporin-2 (AQP2). The hormone binds to vasopressin V2 receptors (V2R) on the surface of the cells and stimulates cAMP synthesis. The cAMP activates protein kinase A (PKA), which initiates signaling that causes an accumulation of AQP2 in the plasma membrane of the cells facilitating water reabsorption from primary urine and fine-tuning of body water homeostasis. AVP-mediated PKA activation also causes an increase in the AQP2 protein abundance through a mechanism that involves dephosphorylation of AQP2 at serine 261 and a decrease in its poly-ubiquitination. However, the signaling downstream of PKA that controls the localization and abundance of AQP2 is incompletely understood. We carried out an siRNA screen targeting 719 kinase-related genes, representing the majority of the kinases of the human genome and analyzed the effect of the knockdown on AQP2 by high-content imaging and biochemical approaches. The screening identified 13 hits whose knockdown inhibited the AQP2 accumulation in the plasma membrane. Amongst the candidates was the so far hardly characterized cyclin-dependent kinase 18 (CDK18). Our further analysis revealed a hitherto unrecognized signalosome comprising CDK18, an E3 ubiquitin ligase, STUB1 (CHIP), PKA and AQP2 that controls the localization and abundance of AQP2. CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. STUB1 functions as an A-kinase anchoring protein (AKAP) tethering PKA to the protein complex and bridging AQP2 and CDK18. The modulation of the protein complex may lead to novel concepts for the treatment of disorders which are caused or are associated with dysregulated AQP2 and for which a satisfactory treatment is not available, e.g., hyponatremia, liver cirrhosis, diabetes insipidus, ADPKD or heart failure.
Noble Metals and Soft Bio-Inspired Nanoparticles in Retinal Diseases Treatment: A Perspective
Authors: De Matteis Valeria , Rizzello Loris
Published: March 2020

We are witnessing an exponential increase in the use of different nanomaterials in a plethora of biomedical fields. We are all aware of how nanoparticles (NPs) have influenced and revolutionized the way we supply drugs or how to use them as therapeutic agents thanks to their tunable physico-chemical properties. However, there is still a niche of applications where NP have not yet been widely explored. This is the field of ocular delivery and NP-based therapy, which characterizes the topic of the current review. In particular, many efforts are being made to develop nanosystems capable of reaching deeper sections of the eye such as the retina. Particular attention will be given here to noble metal (gold and silver), and to polymeric nanoparticles, systems consisting of lipid bilayers such as liposomes or vesicles based on nonionic surfactant. We will report here the most relevant literature on the use of different types of NPs for an efficient delivery of drugs and bio-macromolecules to the eyes or as active therapeutic tools.
Glioblastoma Multiforme Stem Cell Cycle Arrest by Alkylaminophenol through the Modulation of EGFR and CSC Signaling Pathways
Authors: Doan Phuong , Musa Aliyu , Murugesan Akshaya , Sipilä Vili , Candeias Nuno R. , Emmert-Streib Frank , Ruusuvuori Pekka , Granberg Kirsi , Yli-Harja Olli , Kandhavelu Meenakshisundaram
Published: March 2020

Cancer stem cells (CSCs), a small subpopulation of cells existing in the tumor microenvironment promoting cell proliferation and growth. Targeting the stemness of the CSC population would offer a vital therapeutic opportunity. 3,4-Dihydroquinolin-1(2H)-yl)(p-tolyl)methyl)phenol (THTMP), a small synthetic phenol compound, is proposed to play a significant role in controlling the CSC proliferation and survival. We assessed the potential therapeutic effects of THTMP on glioblastoma multiforme (GBM) and its underlying mechanism in various signaling pathways. To fully comprehend the effect of THTMP on the CSCs, CD133+ GBM stem cell (GSC) and CD133- GBM Non-stem cancer cells (NSCC) population from LN229 and SNB19 cell lines was used. Cell cycle arrest, apoptosis assay and transcriptome analysis were performed for individual cell population. THTMP strongly inhibited NSCC and in a subtle way for GSC in a time-dependent manner and inhibit the resistance variants better than that of temozolomide (TMZ). THTMP arrest the CSC cell population at both G1/S and G2/M phase and induce ROS-mediated apoptosis. Gene expression profiling characterize THTMP as an inhibitor of the p53 signaling pathway causing DNA damage and cell cycle arrest in CSC population. We show that the THTMP majorly affects the EGFR and CSC signaling pathways. Specifically, modulation of key genes involved in Wnt, Notch and Hedgehog, revealed the significant role of THTMP in disrupting the CSCs’ stemness and functions. Moreover, THTMP inhibited cell growth, proliferation and metastasis of multiple mesenchymal patient-tissue derived GBM-cell lines. THTMP arrests GBM stem cell cycle through the modulation of EGFR and CSC signaling pathways.
Functional Alterations in Ciliogenesis-Associated Kinase 1 (CILK1) that Result from Mutations Linked to Juvenile Myoclonic Epilepsy
Authors: Wang Eric J. , Gailey Casey D. , Brautigan David L. , Fu Zheng
Published: March 2020

Ciliopathies are a group of human genetic disorders associated with mutations that give rise to the dysfunction of primary cilia. Ciliogenesis-associated kinase 1 (CILK1), formerly known as intestinal cell kinase (ICK), is a conserved serine and threonine kinase that restricts primary (non-motile) cilia formation and length. Mutations in CILK1 are associated with ciliopathies and are also linked to juvenile myoclonic epilepsy (JME). However, the effects of the JME-related mutations in CILK1 on kinase activity and CILK1 function are unknown. Here, we report that JME pathogenic mutations in the CILK1 N-terminal kinase domain abolish kinase activity, evidenced by the loss of phosphorylation of kinesin family member 3A (KIF3A) at Thr672, while JME mutations in the C-terminal non-catalytic domain (CTD) have little effect on KIF3A phosphorylation. Although CILK1 variants in the CTD retain catalytic activity, they nonetheless lose the ability to restrict cilia length and also gain function in promoting ciliogenesis. We show that wild type CILK1 predominantly localizes to the base of the primary cilium; in contrast, JME variants of CILK1 are distributed along the entire axoneme of the primary cilium. These results demonstrate that JME pathogenic mutations perturb CILK1 function and intracellular localization. These CILK1 variants affect the primary cilium, independent of CILK1 phosphorylation of KIF3A. Our findings suggest that CILK1 mutations linked to JME result in alterations of primary cilia formation and homeostasis.
Anomalous Heat Transport in Nanolaminate Metal/Oxide Multilayer Coatings: Plasmon and Phonon Excitations
Authors: Kovalev Anatoly , Wainstein Dmitry , Vakhrushev Vladimir , Gago Raul , Endrino Jose Luis
Published: March 2020

In this work, the anomalous reduction in the thermal conduction observed for nanolaminate metal-dielectric multilayers has been extended to the case of oxides. For this purpose, Ag/Al2O3 coatings were produced with different layer thicknesses (from 1 to 5 nm for Ag and 8 to 40 nm for Al2O3) and numbers of stacks. It was found that the thermal conduction is significantly lower in such metal–oxide nanolaminates compared to the bulk oxide. Such anomalous behaviour is explained by the influence of plasmon and phonon propagation confinement in nanolayers and at the interfaces. To this end, the characteristics of the different types of acoustic and optical phonon waves propagating in the multilayer coating have been studied. In particular, the electronic structures of the different layers and their influences on the plasmon resonance are investigated as a function of the multilayer design. The plasmon-polariton mechanism of energy transfer through oxide–metal and metal–oxide interfaces is discussed.
Microstructure and Wear of (CrN/CrAlN)/(CrAlN/VN) and (CrN/TiAlN)/(TiAlN/VN) Coatings for Molds Used in High Pressure Casting of Aluminum
Authors: Wilczek Aneta , Morgiel Jerzy , Rogal Łukasz , Maziarz Wojciech , Smolik Jerzy
Published: March 2020

Molds made of tool steels used in aluminum high-pressure die casting should routinely withstand tens of thousands of injection cycles, but repeated loading and temperature spikes result in their frequent premature wear. Extending their lifetime could be sought by nitriding or application of coatings of even higher hardness or both. Therefore, in the present experiment the arc-deposited Cr/(CrN)/nx(CrN/CrAlN)/mx(CrAlN/VN) or Cr/(CrN)/nx(CrN/TiAlN)/mx(TiAlN/VN) nano-multilayer stacks were deposited on glow discharge nitrided X40CrMoV5.1 steel. The scanning and transmission electron microscopy backed by Energy Dispersive X-ray Spectroscopy measurements of local chemical composition helped to confirm that the coatings are built of nanolayers of respective nitrides of period less than 10 nm. They also showed that droplets being characteristic for arc deposition method were enriched either in chromium, aluminum or vanadium but not in titanium. Both coatings presented comparable hardness of ~25 GPa, but the one covered with TiAlN/VN was roughly twice as wear resistant as the CrAlN/VN. Simultaneously, they were ~200 and ~100 more wear resistant than X40CrMoV5.1reference steel.
Materials for Orthopedic Bioimplants: Modulating Degradation and Surface Modification Using Integrated Nanomaterials
Authors: Ahirwar Harbhajan , Zhou Yubin , Mahapatra Chinmaya , Ramakrishna Seeram , Kumar Prasoon , Nanda Himansu Sekhar
Published: March 2020

Significant research and development in the field of biomedical implants has evoked the scope to treat a broad range of orthopedic ailments that include fracture fixation, total bone replacement, joint arthrodesis, dental screws, and others. Importantly, the success of a bioimplant depends not only upon its bulk properties, but also on its surface properties that influence its interaction with the host tissue. Various approaches of surface modification such as coating of nanomaterial have been employed to enhance antibacterial activities of a bioimplant. The modified surface facilitates directed modulation of the host cellular behavior and grafting of cell-binding peptides, extracellular matrix (ECM) proteins, and growth factors to further improve host acceptance of a bioimplant. These strategies showed promising results in orthopedics, e.g., improved bone repair and regeneration. However, the choice of materials, especially considering their degradation behavior and surface properties, plays a key role in long-term reliability and performance of bioimplants. Metallic biomaterials have evolved largely in terms of their bulk and surface properties including nano-structuring with nanomaterials to meet the requirements of new generation orthopedic bioimplants. In this review, we have discussed metals and metal alloys commonly used for manufacturing different orthopedic bioimplants and the biotic as well as abiotic factors affecting the failure and degradation of those bioimplants. The review also highlights the currently available nanomaterial-based surface modification technologies to augment the function and performance of these metallic bioimplants in a clinical setting.
Applications of Information Theory Methods for Evolutionary Optimization of Chemical Computers
Authors: Gorecki Jerzy
Published: March 2020

It is commonly believed that information processing in living organisms is based on chemical reactions. However, the human achievements in constructing chemical information processing devices demonstrate that it is difficult to design such devices using the bottom-up strategy. Here I discuss the alternative top-down design of a network of chemical oscillators that performs a selected computing task. As an example, I consider a simple network of interacting chemical oscillators that operates as a comparator of two real numbers. The information on which of the two numbers is larger is coded in the number of excitations observed on oscillators forming the network. The parameters of the network are optimized to perform this function with the maximum accuracy. I discuss how information theory methods can be applied to obtain the optimum computing structure.
Entropy and Information Inequalities
Authors: Jog Varun , Melbourne James
Published: March 2020

Entropy and information inequalities are vitally important in many areas of mathematics and engineering [...]
Relative Distribution Entropy Loss Function in CNN Image Retrieval
Authors: Liu Pingping , Shi Lida , Miao Zhuang , Jin Baixin , Zhou Qiuzhan
Published: March 2020

Convolutional neural networks (CNN) is the most mainstream solution in the field of image retrieval. Deep metric learning is introduced into the field of image retrieval, focusing on the construction of pair-based loss function. However, most pair-based loss functions of metric learning merely take common vector similarity (such as Euclidean distance) of the final image descriptors into consideration, while neglecting other distribution characters of these descriptors. In this work, we propose relative distribution entropy (RDE) to describe the internal distribution attributes of image descriptors. We combine relative distribution entropy with the Euclidean distance to obtain the relative distribution entropy weighted distance (RDE-distance). Moreover, the RDE-distance is fused with the contrastive loss and triplet loss to build the relative distributed entropy loss functions. The experimental results demonstrate that our method attains the state-of-the-art performance on most image retrieval benchmarks.
Maximum Power Point Tracking and Voltage Regulation of Two-Stage Grid-Tied PV System Based on Model Predictive Control
Authors: Ma Miaomiao , Liu Xiangjie , Lee Kwang Y.
Published: March 2020

This paper proposes a maximum power point tracking (MPPT) and voltage regulation method based on model predictive control (MPC) for the two-stage grid-tied photovoltaic (PV) system, which can achieve MPPT and output voltage regulation of a PV system simultaneously. The MPPT algorithm based on MPC is implemented in a DC-DC boost converter. The reference voltage at maximum power point is obtained by dual step Incremental Conductance (I&C) algorithm under the rapidly varying illumination intensity, and the MPPT controller only needs to minimize one cost function of PV current, without pulse width modulation (PWM) module. To inject the generated PV power into the grid with high quality, this paper designs voltage regulation controller based on MPC to maintain the output voltage of the PV system at the desired value. The MPC controller outputs the optimal duty signal with the input and state constraints in the inner loop, and the PI controller in the outer loop is designed to improve the dynamic performance. The proposed method based on MPC was demonstrated using the SimPower systems tool in MATLAB/Simulink. Analysis and simulation results for the PV system show possible improvements on the closed-loop performance such as fast response and low overshoot.