bluuebunny/crossref_metadata_2025 huggingface dataset:
Dual-Specificity Phosphatases in Immunity and Infection: An Update
Authors: Lang Roland , Raffi Faizal
Published: June 2019

Kinase activation and phosphorylation cascades are key to initiate immune cell activation in response to recognition of antigen and sensing of microbial danger. However, for balanced and controlled immune responses, the intensity and duration of phospho-signaling has to be regulated. The dual-specificity phosphatase (DUSP) gene family has many members that are differentially expressed in resting and activated immune cells. Here, we review the progress made in the field of DUSP gene function in regulation of the immune system during the last decade. Studies in knockout mice have confirmed the essential functions of several DUSP-MAPK phosphatases (DUSP-MKP) in controlling inflammatory and anti-microbial immune responses and support the concept that individual DUSP-MKP shape and determine the outcome of innate immune responses due to context-dependent expression and selective inhibition of different mitogen-activated protein kinases (MAPK). In addition to the canonical DUSP-MKP, several small-size atypical DUSP proteins regulate immune cells and are therefore also reviewed here. Unexpected and complex findings in DUSP knockout mice pose new questions regarding cell type-specific and redundant functions. Another emerging question concerns the interaction of DUSP-MKP with non-MAPK binding partners and substrate proteins. Finally, the pharmacological targeting of DUSPs is desirable to modulate immune and inflammatory responses.
High-Pressure Carbon Monoxide and Oxygen Mixture is Effective for Lung Preservation
Authors: Fujiwara Atsushi , Hatayama Naoyuki , Matsuura Natsumi , Yokota Naoya , Fukushige Kaori , Yakura Tomiko , Tarumi Shintaro , Go Tetsuhiko , Hirai Shuichi , Naito Munekazu , Yokomise Hiroyasu
Published: June 2019

(1) Background: Heme oxygenase-1 (HO-1) degrades heme and generates carbon monoxide (CO), producing various anti-inflammatory, anti-oxidative, and anti-apoptotic effects. This study aimed to confirm the effects of CO on the ischemia–reperfusion injury (IRI) of donor lungs using a high-pressure gas (HPG) preservation method. (2) Methods: Donor rat and canine lungs were preserved in a chamber filled with CO (1.5 atm) and oxygen (O2; 2 atm) and were ventilated with either CO and O2 mixture (CO/O2 group) or air (air group) immediately before storage. Rat lungs were subjected to heterotopic cervical transplantation and evaluated after reperfusion, whereas canine lungs were subjected to allogeneic transplantation and evaluated. (3) Results: Alveolar hemorrhage in the CO/O2 group was significantly milder than that in the air group. mRNA expression levels of HO-1 remained unchanged in both the groups; however, inflammatory mediator levels were significantly lower in the CO/O2 group than in the air group. The oxygenation of graft lungs was comparable between the two groups, but lactic acid level tended to be higher in the air group. (4) Conclusions: The HO-1/CO system in the HPG preservation method is effective in suppressing IRI and preserving donor lungs.
Animal Models for Human Polycystic Ovary Syndrome (PCOS) Focused on the Use of Indirect Hormonal Perturbations: A Review of the Literature
Authors: Ryu Youngjae , Kim Sung Woo , Kim Yoon Young , Ku Seung-Yup
Published: June 2019

Hormonal disturbances, such as hyperandrogenism, are considered important for developing polycystic ovary syndrome (PCOS) in humans. Accordingly, directly hormone-regulated animal models are widely used for studying PCOS, as they replicate several key PCOS features. However, the pathogenesis and treatment of PCOS are still unclear. In this review, we aimed to investigate animal PCOS models and PCOS-like phenotypes in animal experiments without direct hormonal interventions and determine the underlying mechanisms for a better understanding of PCOS. We summarized animal PCOS models that used indirect hormonal interventions and suggested or discussed pathogenesis of PCOS-like features in animals and PCOS-like phenotypes generated in other animals. We presented integrated physiological insights and shared cellular pathways underlying the pathogenesis of PCOS in reviewed animal models. Our review indicates that the hormonal and metabolic changes could be due to molecular dysregulations, such as upregulated PI3K-Akt and extracellular signal-regulated kinase (ERK) signalling, that potentially cause PCOS-like phenotypes in the animal models. This review will be helpful for considering alternative animal PCOS models to determine the cellular/molecular mechanisms underlying PCOS symptoms. The efforts to determine the specific cellular mechanisms of PCOS will contribute to novel treatments and control methods for this complex syndrome.
Computation Offloading Strategy in Mobile Edge Computing
Authors: Sheng Jinfang , Hu Jie , Teng Xiaoyu , Wang Bin , Pan Xiaoxia
Published: June 2019

Mobile phone applications have been rapidly growing and emerging with the Internet of Things (IoT) applications in augmented reality, virtual reality, and ultra-clear video due to the development of mobile Internet services in the last three decades. These applications demand intensive computing to support data analysis, real-time video processing, and decision-making for optimizing the user experience. Mobile smart devices play a significant role in our daily life, and such an upward trend is continuous. Nevertheless, these devices suffer from limited resources such as CPU, memory, and energy. Computation offloading is a promising technique that can promote the lifetime and performance of smart devices by offloading local computation tasks to edge servers. In light of this situation, the strategy of computation offloading has been adopted to solve this problem. In this paper, we propose a computation offloading strategy under a scenario of multi-user and multi-mobile edge servers that considers the performance of intelligent devices and server resources. The strategy contains three main stages. In the offloading decision-making stage, the basis of offloading decision-making is put forward by considering the factors of computing task size, computing requirement, computing capacity of server, and network bandwidth. In the server selection stage, the candidate servers are evaluated comprehensively by multi-objective decision-making, and the appropriate servers are selected for the computation offloading. In the task scheduling stage, a task scheduling model based on the improved auction algorithm has been proposed by considering the time requirement of the computing tasks and the computing performance of the mobile edge computing server. Extensive simulations have demonstrated that the proposed computation offloading strategy could effectively reduce service delay and the energy consumption of intelligent devices, and improve user experience.
Polymer Concrete for Bridge Deck Closure Joints in Accelerated Bridge Construction
Authors: Mantawy Islam , Chennareddy Rahulreddy , Genedy Moneeb , Taha Mahmoud Reda
Published: June 2019

Prefabricated concrete bridge deck panels are utilized in Accelerated Bridge Construction (ABC) to simplify bridge deck construction. Concrete with good bond and shear strength as well as excellent flowability is required to fill bridge deck closure joints. This paper discusses the use of polymer concrete (PC) for bridge deck closure joints in ABC. PC produced using poly methyl methacrylate and standard aggregate was tested. Test results of PC are compared to Ultra-High Performance Concrete (UHPC). Development length, lap splice length and shear strength of unreinforced PC were tested. It is shown that PC has a development length of 3.6 to 4.1 times the reinforcing bar diameter that is close to one-half the development length of 6 to 8 times the bar diameter required with UHPC. PC also showed a shorter splice length compared with that reported for UHPC. Finally, unreinforced PC showed shear strength that is twice that of UHPC. It is evident that using PC in bridge deck closure joints in ABC can improve constructability and provide cost-savings and eliminate reinforcing bar congestion.
The Functions of Long Non-Coding RNA during Embryonic Cardiovascular Development and Its Potential for Diagnosis and Treatment of Congenital Heart Disease
Authors: Turton Nadia , Swan Ross , Mahenthiralingam Thanujan , Pitts Dominic , Dykes Iain M.
Published: June 2019

Congenital heart disease (CHD) arises due to errors during the embryonic development of the heart, a highly regulated process involving an interplay between cell-intrinsic transcription factor expression and intercellular signalling mediated by morphogens. Emerging evidence indicates that expression of these protein-coding genes is controlled by a plethora of previously unappreciated non-coding RNAs operating in complex feedback-control circuits. In this review, we consider the contribution of long non-coding RNA (lncRNA) to embryonic cardiovascular development before discussing applications to CHD diagnostics and therapeutics. We discuss the process of lineage restriction during cardiovascular progenitor cell differentiation, as well as the subsequent patterning of the cardiogenic progenitor fields, taking as an example the regulation of NODAL signalling in left-right patterning of the heart. lncRNA are a highly versatile group. Nuclear lncRNA can target specific genomic sequences and recruit chromatin remodelling complexes. Some nuclear lncRNA are transcribed from enhancers and regulate chromatin looping. Cytoplasmic lncRNA act as endogenous competitors for micro RNA, as well as binding and sequestering signalling proteins. We discuss features of lncRNA that limit their study by conventional methodology and suggest solutions to these problems.
Durability of Composite Materials under Severe Temperature Conditions: Influence of Moisture Content and Prediction of Thermo-Mechanical Properties During a Fire
Authors: Márquez Costa Juan Pablo , Legrand Vincent , Fréour Sylvain
Published: June 2019

The main objective of the present study was to develop a fire thermal model able to predict the evolution of the temperature and decomposition gradient across a laminated composite structure when exposed to fire. The thermal response of composite laminate made of organic polymer matrix was investigated under severe temperature conditions as samples were exposed to high temperatures up to 750 °C. The highlight is that a behavior law for water is included in our thermo-mechanical model to estimate effects due to a moisture content field on the thermal response of composite laminates. In particular, porosity and gas pressure are strongly influenced by the presence of water in the material and modify the thermal behavior accordingly. This enabled us to propose a new approach that can be used for the prediction of hygro-thermo-chemico-mechanical post-combustion properties in a very large number of material and fire scenarios.
The Developmental Phases of Zebrafish Myogenesis
Authors: Keenan Samuel R. , Currie Peter D.
Published: June 2019

The development and growth of vertebrate axial muscle have been studied for decades at both the descriptive and molecular level. The zebrafish has provided an attractive model system for investigating both muscle patterning and growth due to its simple axial musculature with spatially separated fibre types, which contrasts to complex muscle groups often deployed in amniotes. In recent years, new findings have reshaped previous concepts that define how final teleost muscle form is established and maintained. Here, we summarise recent findings in zebrafish embryonic myogenesis with a focus on fibre type specification, followed by an examination of the molecular mechanisms that control muscle growth with emphasis on the role of the dermomyotome-like external cell layer. We also consider these data sets in a comparative context to gain insight into the evolution of axial myogenic patterning systems within the vertebrate lineage.
Effect of SLM Build Parameters on the Compressive Properties of 304L Stainless Steel
Authors: Fashanu Okanmisope , Buchely Mario F. , Spratt Myranda , Newkirk Joseph , Chandrashekhara K. , Misak Heath , Walker Michael
Published: June 2019

Selective laser melting (SLM) is well suited for the efficient manufacturing of complex structures because of its manufacturing methodology. The optimized process parameters for each alloy has been a cause for debate in recent years. In this study, the hatch angle and build orientation were investigated. 304L stainless steel samples were manufactured using three hatch angles (0°, 67°, and 105°) in three build orientations (x-, y-, and z-direction) and tested in compression. Analysis of variance and Tukey’s test were used to evaluate the obtained results. Results showed that the measured compressive yield strength and plastic flow stress varied when the hatch angle and build orientation changed. Samples built in the y-direction exhibited the highest yield strength irrespective of the hatch angle; although, samples manufactured using a hatch angle of 0° exhibited the lowest yield strength. Samples manufactured with a hatch angle of 0° flowed at the lowest stress at 35% plastic strain. Samples manufactured with hatch angles of 67° and 105° flowed at statistically the same flow stress at 35% plastic strain. However, samples manufactured with a 67° hatch angle deformed non-uniformly. Therefore, it can be concluded that 304L stainless steel parts manufactured using a hatch angle of 105° in the y-direction exhibited the best overall compressive behavior.
Estimating Connectivity of Hard Clam (Mercenaria mercenaria) and Eastern Oyster (Crassostrea virginica) Larvae in Barnegat Bay
Authors: Goodwin Jacob D. , Munroe Daphne M. , Defne Zafer , Ganju Neil K. , Vasslides James
Published: June 2019

Many marine organisms have a well-known adult sessile stage. Unfortunately, our lack of knowledge regarding their larval transient stage hinders our understanding of their basic ecology and connectivity. Larvae can have swimming behavior that influences their transport within the marine environment. Understanding the larval stage provides insight into population connectivity that can help strategically identify areas for restoration. Current techniques for understanding the larval stage include modeling that combines particle attributes (e.g., larval behavior) with physical processes of water movement to contribute to our understanding of connectivity trends. This study builds on those methods by using a previously developed retention clock matrix (RCM) to illustrate time dependent connectivity of two species of shellfish between areas and over a range of larval durations. The RCM was previously used on physical parameters but we expand the concept by applying it to biology. A new metric, difference RCM (DRCM), is introduced to quantify changes in connectivity under different scenarios. Broad spatial trends were similar for all behavior types with a general south to north progression of particles. The DRCMs illustrate differences between neutral particles and those with behavior in northern regions where stratification was higher, indicating that larval behavior influenced transport. Based on these findings, particle behavior led to small differences (north to south movement) in transport patterns in areas with higher salinity gradients (the northern part of the system) compared to neutral particles. Overall, the dominant direction for particle movement was from south to north, which at times was enhanced by winds from the south. Clam and oyster restoration in the southern portion of Barnegat Bay could serve as a larval supply for populations in the north. These model results show that coupled hydrodynamic and particle tracking models have implications for fisheries management and restoration activities.
A Nourishment Performance Index for Beach Erosion/Accretion at Saadiyat Island in Abu Dhabi
Authors: Hamza Waleed , Tomasicchio Giuseppe Roberto , Ligorio Francesco , Lusito Letizia , Francone Antonio
Published: June 2019

The present paper proposes a methodology to optimise the design of a beach protection intervention at Saadiyat Island, of the Abu Dhabi city in the United Arab Emirates. In particular, a nourishment performance index (NPI) has been introduced to select among different design alternatives of a coastal engineering intervention related to the ongoing development of the island. The NPI is based on general factors such as the initial volume of sand necessary for the nourishment, the beach surface loss after the intervention and the closure depth. The proposed index, properly integrated with a numerical simulation of the beach morphodynamics, is shown to be promising in the evaluation of the feasibility for the planned coastal defence interventions. The adoption of different design scenarios has showed that the NPI value depends mainly on the built nourishment shoreline.
Quasi-Isotropic and Pseudo-Ductile Highly Aligned Discontinuous Fibre Composites Manufactured with the HiPerDiF (High Performance Discontinuous Fibre) Technology
Authors: Longana M. L. , Yu H. , Lee J. , Pozegic T. R. , Huntley S. , Rendall T. , Potter K. D. , Hamerton I.
Published: June 2019

Conventional composite materials reinforced with continuous fibres display high specific strength but have a number of drawbacks including: the elastic-brittle behaviour, difficulties in producing defect-free components of complex shape with high-volume automated manufacturing processes, and inherent lack of recyclability. Highly aligned, discontinuous fibre-reinforced composites (ADFRCs) are truly beneficial for mass production applications, with the potential to offer better formability and comparable mechanical properties with continuous fibre-reinforced composites. In previous publications, the High Performance Discontinuous Fibre (HiPerDiF) technology has been shown to offer the possibility to intimately hybridise different types of fibres, to achieve pseudo-ductile tensile behaviour, and remanufacture reclaimed fibres into high-performance recycled composites. However, to date, the work has been conducted with unidirectional (UD) laminates, which is of limited interest in engineering applications with mechanical stresses acting across many directions; this paper reports, for the first time, the mechanical behaviour of quasi-isotropic (QI) ADFRCs. When compared with randomly-oriented discontinuous fibre composites (RODFRCs), QI ADFRCs offer enhanced stiffness (+26%) and strength (+77%) with higher consistency, i.e., a reduction of the coefficient of variance from the 25% of RODFRCs to the 6% of ADFRCs. Furthermore, hybrid QI ADFRCs retain the pseudo-ductility tensile behaviour previously observed in unidirectional (UD) lay-up.
Coating Techniques for Functional Enhancement of Metal Implants for Bone Replacement: A Review
Authors: Dehghanghadikolaei Amir , Fotovvati Behzad
Published: June 2019

To facilitate patient healing in injuries and bone fractures, metallic implants have been in use for a long time. As metallic biomaterials have offered desirable mechanical strength higher than the stiffness of human bone, they have maintained their place. However, in many case studies, it has been observed that these metallic biomaterials undergo a series of corrosion reactions in human body fluid. The products of these reactions are released metallic ions, which are toxic in high dosages. On the other hand, as these metallic implants have different material structures and compositions than that of human bone, the process of healing takes a longer time and bone/implant interface forms slower. To resolve this issue, researchers have proposed depositing coatings, such as hydroxyapatite (HA), polycaprolactone (PCL), metallic oxides (e.g., TiO2, Al2O3), etc., on implant substrates in order to enhance bone/implant interaction while covering the substrate from corrosion. Due to many useful HA characteristics, the outcome of various studies has proved that after coating with HA, the implants enjoy enhanced corrosion resistance and less metallic ion release while the bone ingrowth has been increased. As a result, a significant reduction in patient healing time with less loss of mechanical strength of implants has been achieved. Some of the most reliable coating processes for biomaterials, to date, capable of depositing HA on implant substrate are known as sol-gel, high-velocity oxy-fuel-based deposition, plasma spraying, and electrochemical coatings. In this article, all these coating methods are categorized and investigated, and a comparative study of these techniques is presented.
Effect of Chemical Treatments on the Properties of High-Density Luffa Mattress Filling Materials
Authors: Zhang Kaiting , Guo Yong , Yuan Fangcheng , Zhang Tingting , Zhu Zhenzhen , Weng Beibei , Wu ShanShan , Chen Tong , Chen Yuxia
Published: June 2019

Luffa is a lightweight porous material with excellent biocompatibility and abundant resources. In this paper, three kinds of softening treatment methods, alkali-hydrogen peroxide (Method 1), alkali-acetic acid (Method 2), and alkali-urea (Method 3), were used to soften high-density (HD) cylindrical luffa (CL) mattress-filling materials (MFM). Microscopic observation, mechanical performance testing and other analyses were performed to evaluate the effects of the three kinds of softening methods on the wettability, compression resilience and support performance of CL MFM. The results showed that: (1) After the treatment by Method 1, Method 2 and Method 3, the peak stress of CL decreased by 73%, 10% and 27%, respectively. In addition, after three kinds of softening treatments, the uniformity of CL increased. (2) When the CL MFM of high density rank treated by Method 1 was compressed by 40%, the firmness values of the surface, core and bottom reduced by 53.49% 40.72%, and 46.17%, respectively, compared to that of untreated CL. In addition, for the CL MFM of high density rank treated by Method 3 and then compressed to 60%, the firmness of the surface layer, core layer and bottom layer reduced by 41.2%, 33.7%, and 36.9%, respectively. (3) The contact angle of luffa treated by Method 3 was the smallest, next came Method 1 and Method 2, and untreated was the largest. (4) After the treatment by Method 3, the fiber bundle of luffa was intact, and the compression resilience of the CL was obviously increased. Therefore, this method can effectively reduce the firmness of MFM and also improve the uniformity and wettability of CL.
Effects of Polypropylene Fibre and Strain Rate on Dynamic Compressive Behaviour of Concrete
Authors: Chen Meng , Ren Chenhui , Liu Yangbo , Yang Yubo , Wang Erlei , Liang Xiaolong
Published: June 2019

This paper presents an experimental study on the dynamic compressive behaviour of polypropylene (PP) fibre reinforced concrete under various strain rates using split Hopkinson pressure bar (SHPB) equipment. The effects of PP fibre content and strain rate on the dynamic compressive stress-strain relationship and failure patterns were estimated. The results indicated that the addition of PP fibre enhanced the dynamic compressive properties of concrete mixtures although it resulted in a significant reduction in workability and a slight decrease in static compressive strength. Considering the workability, static compressive strength and dynamic compressive behaviour, the optimal PP fibre content was found to be 0.9 kg/m3 as the mixture exhibited the highest increase in dynamic compressive strength of 5.6%, 40.3% in fracture energy absorption and 11.1% in total energy absorption; further, it showed the least reduction (only 5.8%) in static compressive strength among all mixtures compared to the reference mixture without fibre. For all mixtures, the dynamic compressive properties, energy absorption capacity, strain at peak stress, ultimate strain and dynamic increase factor (DIF) were significantly influenced by strain rate, i.e., strain rate effect. When the strain rate was relatively low, PP fibres were effective in controlling the cracking, and the dynamic compressive properties of PP fibre reinforced mixtures were improved accordingly.
Investigation on the Mechanical Properties of MRE Compounds
Authors: Brancati Renato , Di Massa Giandomenico , Pagano Stefano
Published: June 2019

This paper describes an experimental investigation conducted on magneto-rheological elastomers (MREs) with the aim of adopting these materials to make mounts to be used as vibration isolators. These materials, consisting of an elastomeric matrix containing ferromagnetic particles, are considered to be smart materials, as it is possible to control their mechanical properties by means of an applied magnetic field. In the first part of the paper, the criteria adopted to define the characteristics of the material and the experimental procedures for making samples are described. The samples are subjected to a compressive static test and are then, adopting a testing machine specially configured, tested for shear periodic loads, each characterized by a different constant compressive preload. The testing machine is equipped with a coil, with which it is possible to vary the intensity of the magnetic field crossing the sample during testing to evaluate the magneto-rheological effect on the materials’ characteristics in terms of stiffness and damping.
Banach-Space Operators Acting on Semicircular Elements Induced by p-Adic Number Fields over Primes p
Authors: Cho Ilwoo
Published: June 2019

In this paper, we study certain Banach-space operators acting on the Banach *-probability space ( LS , τ 0 ) generated by semicircular elements Θ p , j induced by p-adic number fields Q p over the set P of all primes p. Our main results characterize the operator-theoretic properties of such operators, and then study how ( LS , τ 0 ).
Semi-Idempotents in Neutrosophic Rings
Authors: Kandasamy W.B. Vasantha , Kandasamy Ilanthenral , Smarandache Florentin
Published: June 2019

In complex rings or complex fields, the notion of imaginary element i with i 2 = − 1 or the complex number i is included, while, in the neutrosophic rings, the indeterminate element I where I 2 = I is included. The neutrosophic ring ⟨ R ∪ I ⟩ is also a ring generated by R and I under the operations of R. In this paper we obtain a characterization theorem for a semi-idempotent to be in ⟨ Z p ∪ I ⟩ , the neutrosophic ring of modulo integers, where p a prime. Here, we discuss only about neutrosophic semi-idempotents in these neutrosophic rings. Several interesting properties about them are also derived and some open problems are suggested.
Anti-Inflammatory Effects of 5α,8α-Epidioxycholest-6-en-3β-ol, a Steroidal Endoperoxide Isolated from Aplysia depilans, Based on Bioguided Fractionation and NMR Analysis
Authors: Pereira Renato B. , Pereira David M. , Jiménez Carlos , Rodríguez Jaime , Nieto Rosa M. , Videira Romeu A. , Silva Olga , Andrade Paula B. , Valentão Patrícia
Published: June 2019

Sea hares of Aplysia genus are recognized as a source of a diverse range of metabolites. 5α,8α-Endoperoxides belong to a group of oxidized sterols commonly found in marine organisms and display several bioactivities, including antimicrobial, anti-tumor, and immunomodulatory properties. Herein we report the isolation of 5α,8α-epidioxycholest-6-en-3β-ol (EnP(5,8)) from Aplysia depilans Gmelin, based on bioguided fractionation and nuclear magnetic resonance (NMR) analysis, as well as the first disclosure of its anti-inflammatory properties. EnP(5,8) revealed capacity to decrease cellular nitric oxide (NO) levels in RAW 264.7 macrophages treated with lipopolysaccharide (LPS) by downregulation of the Nos2 (inducible nitric oxide synthase, iNOS) gene. Moreover, EnP(5,8) also inhibited the LPS-induced expression of cyclooxygenase-2 (COX-2), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) at the mRNA and protein levels. Mild selective inhibition of COX-2 enzyme activity was also evidenced. Our findings provide evidence of EnP(5,8) as a potential lead drug molecule for the development of new anti-inflammatory agents.
Gentisyl Alcohol Inhibits Proliferation and Induces Apoptosis via Mitochondrial Dysfunction and Regulation of MAPK and PI3K/AKT Pathways in Epithelial Ovarian Cancer Cells
Authors: Ham Jiyeon , Lim Whasun , Kim Kyeongwon , Heo Young Mok , Ryu Seung Mok , Lee Dongho , Kim Jae-Jin , Song Gwonhwa
Published: June 2019

Ovarian cancer is one of the prevalent gynecological cancers occurring in women. In particular, the efficiency of standard therapeutic methods decreases when recurrence and chemoresistance ensue. To assist standard anti-cancer agents in the cure of ovarian cancer, development and application of new compounds such as small molecules or natural products are required. Gentisyl alcohol is one of the secondary metabolites that can be obtained by purification from bacteria or fungi and is known to have antibacterial, antifungal, antiviral, and anti-cancer effects. In the present study, we verified the effect of gentisyl alcohol derived from marine Arthrinium sp. on suppressing proliferation and inducing apoptosis via DNA fragmentation in human ovarian cancers cells (ES2 and OV90 cells). We also confirmed that there was an accumulation of sub-G1 cells and a loss of mitochondrial membrane potential with calcium dysregulation in gentisyl alcohol-treated ovarian cancer cells. Moreover, gentisyl alcohol up-regulated signal transduction of MAPK and PI3K/AKT pathways. Collectively, our results demonstrated the possibility of gentisyl alcohol as a novel therapeutic agent for human ovarian cancer.
Time from Symptom Onset to Diagnosis and Treatment among Haematological Malignancies: Influencing Factors and Associated Negative Outcomes
Authors: Dapkevičiūtė Austėja , Šapoka Virginijus , Martynova Elena , Pečeliūnas Valdas
Published: June 2019

Background and objectives: Diagnostic delay causes unfavorable outcomes among cancer patients. It has been widely analyzed in solid tumors. However, data regarding hematological malignancies diagnostic delay are scarce. We aimed to evaluate diagnostic intervals, their influencing factors, and the negative effect on clinical outcomes among multiple myeloma and lymphoma patients. Materials and methods: One hundred patients diagnosed with multiple myeloma (n = 53) or lymphoma (n = 47) (ICD codes—C90, C81–C84) were asked to participate during their scheduled hematology consultations. Interval durations and the majority of influencing factors were assessed based on a face-to-face questionnaire. Data of disease characteristics were collected from medical records. Results: The median interval from symptom onset to registration for medical consultation was 30 (0–730) days, from registration to consultation 2 (0–30) days, from first consultation to diagnosis 73 (6–1779) days, and from diagnosis to treatment 5 (0–97) days. Overall time to diagnosis median was 151 (23–1800) days. Factors significantly prolonging diagnostic intervals in multivariate linear regression were living in big cities (p = 0.008), anxiety and depression (p = 0.002), self-medication (p = 0.019), and more specialists seen before diagnosis (p = 0.022). Longer diagnostic intervals resulted in higher incidences of multiple myeloma complications (p = 0.024) and more advanced Durie-Salmon stage (p = 0.049), but not ISS stage and Ann-Arbor staging systems for lymphomas. Conclusion: Median overall diagnostic delay was nearly 5 months, indicating that there is room for improvement. The most important factors causing delays were living in big cities, anxiety and depression, self-medication, and more specialists seen before diagnosis. Diagnostic delay may have a negative influence on clinical outcomes for multiple myeloma patients.
Quality of Life and Female Sexual Dysfunction in Croatian Women with Stress-, Urgency- and Mixed Urinary Incontinence: Results of a Cross-Sectional Study
Authors: Radoja Ivan , Degmečić Dunja
Published: June 2019

Background and objectives: Urinary incontinence is defined as the involuntary leakage of urine. Studies have reported that the severity of urinary incontinence symptoms can cause decreased quality of life and female sexual dysfunction in women, but the association between the duration of the incontinence and the aforementioned disturbances has not been evaluated. The objective of this study was to evaluate the differences in the occurrence of decreased quality of life and female sexual dysfunction in Croatian women with urinary incontinence, with regard to the duration and subtype of urinary incontinence. Materials and Methods: We conducted a cross-sectional study from March 2017 to July 2018 at our neurourology and urodynamics outpatient clinic, among 120 women with urinary incontinence symptoms. Based on medical history, physical exam and urodynamic assessment, participants were divided into groups with stress-, urgency- and mixed urinary incontinence. Several quality of life and female sexual dysfunction questionnaires were used for evaluation. The differences between the three UI groups were tested by the Kruskal–Wallis test. All p values were two-sided. The level of significance was set to Alpha = 0.05. Results: The mixed urinary incontinence group had a significantly inferior quality of life (p = 0.003) and lower scores on the female sexual dysfunction questionnaires (p = 0.02). The longer the duration of incontinence King’s Health Questionnaire total score was worse (p = 0.003) and Female Sexual Function Index total score was worse (p < 0.001). Conclusions: Our results showed that there was a statistically significant difference in the occurrence of decreased quality of life and female sexual dysfunction considering the duration and subtype of incontinence in Croatian women.
Resting Energy Expenditure and Protein Balance in People with Epidermolysis Bullosa
Authors: Zidorio Ana Paula , Togo Camille , Jones Rosie , Dutra Eliane , de Carvalho Kenia
Published: June 2019

Epidermolysis bullosa (EB) is a group of conditions characterized by severe fragility of the skin that causes recurring blistering. The recessive dystrophic subtype of EB (RDEB) has a strong impact on the nutritional status. We evaluated the resting energy expenditure (REE) and presence of protein catabolism in patients with RDEB. REE was assessed in 10 subjects (7 females; age range 4–33 years) by indirect calorimetry and using a predictive equation. Nitrogen balance was calculated by protein intake and 24 h urinary urea excretion estimations. An assessment of body surface area (BSA) with infected and non-infected skin lesions was applied to the nitrogen balance burn equation that was adapted to EB. The REE values predicted by the equation were consistently lower than the ones measured, except for two subjects. All subjects recorded high protein and energy intake, with protein intake being higher than 4 g protein/kg/day for five subjects. Even so, protein catabolism was observed in six subjects, three of whom had infected wounds. This study raises the hypothesis that the clinical and nutritional risks of people with RDEB are associated with an increased REE and negative nitrogen balance, which reinforces the importance of nutritional support.
Assessment of Vitamin D Supplementation on Articular Cartilage Morphology in a Young Healthy Sedentary Rat Model
Authors: Szychlinska Marta Anna , Imbesi Rosa , Castrogiovanni Paola , Guglielmino Claudia , Ravalli Silvia , Di Rosa Michelino , Musumeci Giuseppe
Published: June 2019

Deficiency in vitamin D (Vit D) has been widely associated with several musculoskeletal diseases. However, the effects of the exogenous Vit D supplementation are still unclear in the prevention of the latter, especially in the cartilage developmental period. The aim of this study was to compare the effects of Vit D supplementation and restriction on the articular cartilage development in healthy young sedentary rats. To this aim, twelve nine-week-old healthy Sprague–Dawley male rats were subjected to Vit D-based experimental diets: R, with a content in Vit D of 1400 IU/kg; R-DS, with a Vit D supplementation (4000 IU/kg); R-DR, with a Vit D restriction (0 IU/kg) for 10 weeks. The morphology, thickness and expression of cartilage-associated molecules such as collagen type II/X, lubricin and Vit D receptor (VDR), were assessed. Histological, histomorphometric and immunohistochemical evaluations were made on rat tibial cartilage samples. In the present experimental model, restriction of Vit D intake induced: The lower thickness of cartilage compared both to R (p = < 0.0001) and R-DS (p = < 0.0001); reduction of proteoglycans in the extracellular matrix (ECM) compared both to R (p = 0.0359) and R-DS (p = < 0.0001); decreased collagen II (Col II) with respect both to R (p = 0.0076) and R-DS (p = 0.0016); increased collagen X (Col X) immunoexpression when compared both to R (p = < 0.0001) and R-DS (p = < 0.0001), confirming data from the literature. Instead, supplementation of Vit D intake induced: Higher cartilage thickness with respect both to R (p = 0.0071) and R-DR (p = < 0.0001); increase of ECM proteoglycan deposition compared both to R (p = 0.0175) and R-DR (p = < 0.0001); higher immunoexpression of lubricin with respect both to R (p = 0.001) and R-DR (p = 0.0008). These results suggest that Vit D supplementation with diet, already after 10 weeks, has a favorable impact on the articular cartilage thickness development, joint lubrication and ECM fibers deposition in a young healthy rat model.
De Novo Design and In Vitro Testing of Antimicrobial Peptides against Gram-Negative Bacteria
Authors: Vishnepolsky Boris , Zaalishvili George , Karapetian Margarita , Nasrashvili Tornike , Kuljanishvili Nato , Gabrielian Andrei , Rosenthal Alex , Hurt Darrell E. , Tartakovsky Michael , Grigolava Maya , Pirtskhalava Malak
Published: June 2019

Antimicrobial peptides (AMPs) have been identified as a potentially new class of antibiotics to combat bacterial resistance to conventional drugs. The design of de novo AMPs with high therapeutic indexes, low cost of synthesis, high resistance to proteases and high bioavailability remains a challenge. Such design requires computational modeling of antimicrobial properties. Currently, most computational methods cannot accurately calculate antimicrobial potency against particular strains of bacterial pathogens. We developed a tool for AMP prediction (Special Prediction (SP) tool) and made it available on our Web site (https://dbaasp.org/prediction). Based on this tool, a simple algorithm for the design of de novo AMPs (DSP) was created. We used DSP to design short peptides with high therapeutic indexes against gram-negative bacteria. The predicted peptides have been synthesized and tested in vitro against a panel of gram-negative bacteria, including drug resistant ones. Predicted activity against Escherichia coli ATCC 25922 was experimentally confirmed for 14 out of 15 peptides. Further improvements for designed peptides included the synthesis of D-enantiomers, which are traditionally used to increase resistance against proteases. One synthetic D-peptide (SP15D) possesses one of the lowest values of minimum inhibitory concentration (MIC) among all DBAASP database short peptides at the time of the submission of this article, while being highly stable against proteases and having a high therapeutic index. The mode of anti-bacterial action, assessed by fluorescence microscopy, shows that SP15D acts similarly to cell penetrating peptides. SP15D can be considered a promising candidate for the development of peptide antibiotics. We plan further exploratory studies with the SP tool, aiming at finding peptides which are active against other pathogenic organisms.
Physiologically Relevant In Vitro-In Vivo Correlation (IVIVC) Approach for Sildenafil with Site-Dependent Dissolution
Authors: Kim Tae Hwan , Shin Soyoung , Jeong Seok Won , Lee Jong Bong , Shin Beom Soo
Published: June 2019

This study aimed to establish a physiologically relevant in vitro-in vivo correlation (IVIVC) model reflecting site-dependent dissolution kinetics for sildenafil based on population-pharmacokinetic (POP-PK) modeling. An immediate release (IR, 20 mg) and three sustained release (SR, 60 mg) sildenafil tablets were prepared by wet granulation method. In vitro dissolutions were determined by the paddle method at pH 1.2, 4.5, and 6.8 media. The in vivo pharmacokinetics were assessed after oral administration of the prepared IR and SR formulations to Beagle dogs (n = 12). The dissolution of sildenafil from SR formulations was incomplete at pH 6.8, which was not observed at pH 1.2 and pH 4.5. The relative bioavailability was reduced with the decrease of the dissolution rate. Moreover, secondary peaks were observed in the plasma concentration-time curves, which may result from site-dependent dissolution. Thus, a POP-PK model was developed to reflect the site-dependent dissolution by separately describing the dissolution and absorption processes, which allowed for estimation of the in vivo dissolution of sildenafil. Finally, an IVIVC was established and validated by correlating the in vitro and in vivo dissolution rates. The present approach may be applied to establish IVIVC for various drugs with complex dissolution kinetics for the development of new formulations.
Comprehensive Study of Intermediate and Critical Quality Attributes for Process Control of High-Shear Wet Granulation Using Multivariate Analysis and the Quality by Design Approach
Authors: Han Jong Kwon , Shin Beom Soo , Choi Du Hyung
Published: June 2019

A robust manufacturing process and the relationship between intermediate quality attributes (IQAs), critical quality attributes (CQAs), and critical process parameters (CPPs) for high-shear wet granulation was determined in this study. Based on quality by the design (QbD) approach, IQAs, CQAs, and CPPs of a telmisartan tablet prepared by high-shear wet granulation were determined and then analyzed with multivariate analysis (MVA) to evaluate mutual interactions between IQAs, CQAs, and CPPs. The effects of the CPPs on the IQAs and CQAs were quantitatively predicted with empirical models of best fit. The models were used to define operating space, and an evaluation of the risk of uncertainty in model prediction was performed using Monte Carlo simulation. MVA showed that granule size and granule hardness were significantly related to % dissolution. In addition, granule FE (Flow Energy) and Carr’s index had effects on tablet tensile strength. Using the manufacture of a clinical batch and robustness testing, a scale-up from lab to pilot scale was performed using geometric similarity, agitator torque profile, and agitator tip speed. The absolute biases and relative bias percentages of the IQAs and CQAs generated by the lab and pilot scale process exhibited small differences. Therefore, the results suggest that a risk reduction in the manufacturing process can be obtained with integrated process parameters as a result of the QbD approach, and the relationship between IQAs, CQAs, and CPPs can be used to predict CQAs for a control strategy and SUPAC (Scale-Up and Post-Approval Guidance).
Ampholytic and Polyelectrolytic Starch as Matrices for Controlled Drug Delivery
Authors: Benyerbah Nassim , Ispas-Szabo Pompilia , Sakeer Khalil , Chapdelaine Daniel , Mateescu Mircea Alexandru
Published: June 2019

The potential of the polyampholytic and polyelectrolytic starch compounds as excipients for drug controlled release was investigated using various tracers differing in terms of solubility and permeability. Ampholytic trimethylaminecarboxymethylstarch (TMACMS) simultaneously carrying trimethylaminehydroxypropyl (TMA) cationic groups and carboxymethyl (CM) anionic groups was obtained in one-step synthesis in aqueous media. Trimethylaminestarch (TMAS) and carboxymethylstarch (CMS) powders were also synthesized separately and then homogenized at equal proportions in liquid phase for co-processing by spray drying (SD) to obtain polyelectrolytic complexes TMAS-CMS (SD). Similarly, equal amounts of TMAS and CMS powders were dry mixed (DM) to obtain TMAS:CMS (DM). Monolithic tablets were obtained by direct compression of excipient/API mixes with 60% or 80% drug loads. The in vitro dissolution tests showed that ampholytic (TMACMS) and co-processed TMAS-CMS (SD) with selected tracers (one from each class of Biopharmaceutical Classification System (BCS)), were able to control the release even at very high loading (80%). The presence of opposite charges located at adequate distances may impact the polymeric chain organisation, their self-assembling, and implicitly the control of drug release. In conclusion, irrespective of preparation procedure, ampholytic and polyelectrolytic starch materials exhibited similar behaviours. Electrostatic interactions generated polymeric matrices conferring good mechanical features of tablets even at high drug loading.
Superhydrophobic Substrates for Ultrahigh Encapsulation of Hydrophilic Drug into Controlled-Release Polyelectrolyte Complex Beads: Statistical Optimization and In Vivo Evaluation
Authors: Yousry Carol , Ahmed Iman S. , Amin Maha M. , El Gazayerly Omaima N.
Published: June 2019

In this work, ultrahigh drug-loaded chitosan (Ch)/K-carrageenan (Kc) polyelectrolyte complex (PEC) beads were formed in situ by cross-linking in a glutaraldehyde-saturated atmosphere and were prepared on superhydrophobic substrates fabricated by spraying glass surfaces with ready-made spray for domestic use (NeverWet®). Verapamil hydrochloride (VP), a highly hydrophilic drug with a short biological half-life, was incorporated into a series of Ch-based and/or Ch/Kc-PEC-based beads to control its release profile in vivo. The formulation of VP-loaded beads was optimized using stepwise statistical designs based on a prespecified criterion. Several characteristics of the prepared beads, such as entrapment efficiency (EE%), in vitro drug release, swelling ratio, size and surface microstructure as well as molecular interactions between the drug and formulation ingredients, were investigated. In vivo pharmacokinetic (PK) studies were carried out using the rabbit model to study the ability of the optimized VP-loaded beads to control the absorption rate of VP. Results revealed that the prepared superhydrophobic substrates were able to fabricate VP-loaded beads with extremely high EE exceeding 90% w/w compared to only 27.80% when using conventional ionotropic gelation technique. PK results showed that the rate of VP absorption was well controlled following oral administration of the optimized beads to six rabbits compared to a marketed VP immediate release (IR) tablet, as evidenced by a 2.2-fold increase in mean residence time (MRT) and 5.24-fold extension in half value duration (HVD) over the marketed product without any observed reduction in the relative oral bioavailability.
Radiation Degradation of β-Glucan with a Potential for Reduction of Lipids and Glucose in the Blood of Mice
Authors: Long Nguyen Thanh , Anh Nguyen Thi Ngoc , Giang Bach Long , Son Hoang Nghia , Luan Le Quang
Published: June 2019

Water-soluble and low molecular weight (Mw) β-glucans were successfully prepared by γ-irradiation of water-insoluble yeast β-glucans. The radiation dose used for the degradation of yeast β-glucan was remarkably reduced by increasing the pH of the sample or combining with hydrogen peroxide treatment. Radiation-degraded β-glucans with molecular weights in the range of 11−48 kDa reduced the total cholesterol, triglyceride, low density lipoprotein (LDL) cholesterol, and glucose levels in the blood of administered mice. The decreasing levels of both lipid and glucose indexes in the blood of tested mice strongly depended on the molecular weight of the β-glucan, and the radiation-degraded β-glucan with a molecular weight of about 25 kDa was found to be the most effective for the reduction of blood lipid and glucose levels. Particularly, the oral administration of 25 kDa β-glucan, with a daily dose of about 2 mg per head, reduced the total cholesterol, triglyceride, LDL-cholesterol, and glucose levels in the blood of tested mice to about 47.4%, 48.5%, 45.7%, and 47.2%, respectively. The effects on the reduction of blood lipid and glucose levels were also found to be stable after 20 days of stopping administration. These results indicate that the degraded β-glucan with a molecular weight of about 25 kDa prepared by γ-ray irradiation is a very promising ingredient that can be used in nutraceutical food for therapeutics of diabetic and dyslipidemia.