bluuebunny/crossref_metadata_2025 huggingface dataset:
Data Center Network Design for Internet‐Related Services and Cloud Computing
Authors: Liang Yong , Lu Mengshi , Shen Zuo‐Jun Max , Tang Runyu
Published: January 2021

Data center networks provide the physical infrastructure that hosts Internet‐related services and cloud computing. Designing data center networks properly is imperative for Internet‐related service and cloud computing providers to gain competitive edges through cost efficiency and service quality. In this study, we formulate a mathematical programming model to address the data center network design problem, in which the objective is to minimize total operating cost and the service delay penalty by optimizing data center location, footprint allocation, and resource provisioning decisions, while incorporating essential features, such as latency, power, multiple resources, configuration limits, and interdependent footprints. We employ a queueing model to approximate the service latency and provide tractable reformulations. To enhance computational efficiency for large‐scale problems, we further develop Lagrangian relaxation methods and generate strengthening cuts by exploiting the structural properties of the problem. Our numerical studies demonstrate that the proposed model, which jointly optimizes location, allocation, and resource provisioning, can achieve significant cost reductions and improvements in service quality compared with a hierarchical approach that optimizes these decisions sequentially. Moreover, our proposed solution methods outperform state‐of‐the‐art commercial software in terms of computational efficiency. Based on real‐world datasets, the proposed model selects data centers that have been chosen by major cloud computing infrastructure providers. We also draw managerial insights that can be used as design guidelines in practice.
Constant Job‐Allowance Policies for Appointment Scheduling: Performance Bounds and Numerical Analysis
Authors: Zhou Shenghai , Ding Yichuan , Huh Woonghee Tim , Wan Guohua
Published: January 2021

We consider the classical appointment scheduling problem that does not have a session length constraint. The decision is to determine job allowances to minimize total expected weighted costs of waiting times of jobs and idle times of the service provider. In particular, we study a simple yet effective scheduling policy—the so‐called “constant" policy, which allocates a constant job allowance for each appointment. Prior studies on appointment scheduling suggest a “dome”‐shaped structure for the optimal job allowance over the planning horizon. This implies that job allowance does not vary significantly in the middle of the schedule sequence, but varies at the beginning as well as the end of the optimal schedule. We show that an even simple scheduling policy—the constant policy, is asymptotically optimal thus provide theoretical justification for such a widely used policy. Using a dynamic programming formulation, we express each job's waiting time as the maximum of a random walk, which allows us to bound the performance gap between the constant policy and the optimal schedule based on classical results on D/ G/1 queues. We derive an explicit upper bound for the performance gap when either of the following conditions holds: (i) the server idling cost is relatively small compared to the job waiting cost, and (ii) the number of appointments is sufficiently large. We also extend this result to a more general setting with multiple service types. Numerical experiments show that the constant policy is near optimal even when the number of appointments is small or when the server idling cost is moderately large, which complements our theoretical results. Our result provides a justification and strong support for the constant policy under certain mild conditions. Moreover, with minor modifications, the constant policy can be adapted to more general scenarios with patient no‐shows, or with heterogeneous appointment types.
Ultrasound appearances and histological correlation of native arteriovenous fistula stenoses – A retrospective case series
Authors: Steiner Kate , Ramanarayanan Sivaramakrishnan , Metcalfe Matthew , Jeevaratnum Praveen , Selvakumar Sadasivam , Narula Ashish
Published: January 2021

The pathophysiology of haemodialysis arteriovenous fistulae (AVF) stenoses is not fully understood. The aim of this study was to perform histology assessment of stenoses in native AVF and compare and correlate the findings between ultrasound and histology. Intimal medial thickness (IMT) was measured on ultrasound where there was measurable neointimal hyperplasia at the site of stenosis and percentage intimal thickening calculated. Ultrasound findings were then compared with histology analysis of AVF stenoses in nine patients. In this small sample, different sonographic appearances and histology were demonstrated. Ultrasound demonstrated stenoses with neointimal hyperplasia and those with no measurable neointimal hyperplasia. Percentage intimal thickening was between 0% and 100%. The histology of the de novo stenoses (where no previous radiological or surgical procedure was performed) demonstrated stenoses with neointimal hyperplasia, no neointimal hyperplasia and neointimal hyperplasia and fibrosis. The histology findings after percutaneous angioplasty (PTA) demonstrated stenoses with neointimal hyperplasia and fibrosis and a stenosis with an acute inflammatory reaction. The findings in this small sample demonstrated that AVF stenoses are not a uniform group as demonstrated by different sonographic and corresponding appearances at histology. Ultrasound appearances of neointimal hyperplasia appear to correlate with neointimal hyperplasia on histology. These findings warrant further investigation and may have implications for treatment strategies.
Polyoxyethylene/polyoxypropylene dimethyl ether (EPDME) random copolymer improves lipid structural ordering in stratum corneum of an epidermal‐equivalent model as seen by two‐photon microscopy
Authors: Umino Yuki , Ipponjima Sari , Denda Mitsuhiro
Published: January 2021

Background/Purpose

Topical application of polyoxyethylene/polyoxypropylene dimethyl ether (EPDME) random copolymer improves the barrier function of skin, whereas polyethylene glycol (PEG) and polypropylene glycol (PPG) are ineffective. The aim of this work was to examine the interaction between these polymers and lipid molecules in the stratum corneum in order to establish whether EPDME‐specific changes in the structural ordering of lipids might account for the improvement of barrier function.

Methods

We used two‐photon microscopy to evaluate the effects of EPDME, PEG, and PPG on the structural ordering of lipids in an epidermal‐equivalent model in terms of the fluorescence changes of Laurdan, a fluorescent dye that responds to changes of membrane fluidity. The generalized polarization (GP) value, a parameter that reflects lipid ordering, was measured at various depths from the surface of the stratum corneum.

Results

EPDME increased the GP value to a depth of about 3 µm from the surface, indicating that lipid ordering was increased in this region, while PEG and PPG of the same molecular weight had no effect. Diffusion of Lucifer yellow into the epidermis was reduced after application of EPDME, indicating that the barrier function was improved.

Conclusion

These results support the view that EPDME improves barrier function by increasing the ordering of lipid structures in the stratum corneum. The methodology described here could be useful for screening new compounds that would improve the structural ordering of lipids.
Convex transform order of Beta distributions with some consequences
Authors: Arab Idir , Oliveira Paulo Eduardo , Wiklund Tilo
Published: January 2021

The convex transform order is one way to make precise comparison between the skewness of probability distributions on the real line. We establish a simple and complete characterization of when one Beta distribution is smaller than another according to the convex transform order. As an application, we derive monotonicity properties for the probability of Beta distributed random variables exceeding the mean or mode of their distribution. Moreover, we obtain a simple alternative proof of the mode‐median‐mean inequality for unimodal distributions that are skewed in a sense made precise by the convex transform order. This new proof also gives an analogous inequality for the anti‐mode of distributions that have a unique anti‐mode. Such inequalities for Beta distributions follow as special cases. Finally, some consequences for the values of distribution functions of binomial distributions near to their means are mentioned.
Filmic encounters: Multispecies care and sacrifice on island Timor
Authors: Palmer Lisa
Published: January 2021

This is a story about the ‘arts of noticing’ more‐than‐human noticing. In it I reflect on the ways in which my own practice of ethnographic filmmaking is itself an agent of multisensory participation. As artifice and artificial eye, there is something both liberating and sensuous about filmmaking practice. It heightens the performativity of participants and their embodied rituals and allows me to enter intimate spaces I would otherwise not encounter. In these encounters a deep multispecies noticing takes place, although in the first instance this is usually only by the camera. The intimacy enabled in these artificial but sensorial encounters can be both revealing and confronting, especially in cases of animal sacrifice. Re‐encountering footage filmed across years of research‐led endeavour, in this paper I explore the power of film to convey these multisensory and multispecies stories, as well as to evoke understanding and engage the multisensory memory of the filmmaker.
Labour demand in global value chains: Is there a bias against unskilled work?
Authors: Reijnders Laurie S. M. , Timmer Marcel P. , Ye Xianjia
Published: January 2021

Rodrik (2018) hypothesises that technology used in global value chains (GVCs) is biased against the use of unskilled workers. To test this hypothesis, we introduce a GVC production function in which final output is produced by means of factor inputs from all countries that participate in the GVC. In contrast, previous studies only consider one stage of production using inputs from a single country. We derive substitution elasticities and labour demand bias in a system of translog GVC cost equations. We find that technical change in GVCs was strongly biased against the use of low‐educated workers, neutral for middle‐educated workers and in favour of high‐educated workers. We show that the biases moderate the potential of GVCs to increase demand for low‐educated workers in low‐income countries.
Cling together, swing together: The contagious effects of COVID‐19 on developing countries through global value chains
Authors: Pahl Stefan , Brandi Clara , Schwab Jakob , Stender Frederik
Published: January 2021

This paper aims at estimating the economic vulnerability of developing countries to disruptions in global value chains (GVCs) due to the COVID‐19 pandemic. It uses trade in value‐added data for a sample of 12 developing countries in sub‐Saharan Africa, Asia and Latin America to assess their dependence on demand and supply from the three main hubs China, Europe and North America. Using first estimates on COVID‐19‐induced changes in final demand and production, we obtain an early projection of the GDP effect during the lockdowns that runs through trade in GVCs. Our estimates reveal that adverse demand‐side effects reduce GDP up to 5.4 per cent, and that collapsing foreign supply puts an even larger share of countries' GDP at risk. Overall, we confirm conjecture that the countries most affected are those highly integrated in GVCs (South‐East Asian countries). We argue, however, that these countries also benefit from a well‐diversified portfolio of foreign suppliers and demand destinations, possibly leading to a cushioning of economic downswing because COVID‐19 stroke major hubs at different times.
Electroretinography (ERG) in the wild giant panda (Ailuropoda melanoleuca)
Authors: Tu Shaotong , Jin Yipeng , Wei Jiaqi , Pan Shiyue , Xiao Xingping , Lin Jiahao
Published: January 2021

Purpose

Using a quick electroretinography (ERG) protocol for rapid assessment of the retinal function of wild giant pandas (Ailuropoda melanoleuca) performed in field conditions to demonstrate the range of ERG recordings in giant pandas of unknown retinal status.

Animals studied

Nine free range giant pandas.

Procedure

All the giant pandas were anesthetized using an intramuscular dexMTZ injection, which is a combination of dexmedetomidine and tiletamine‐zolazepam. After 20 mins of dark adaptation, scotopic ERGs were obtained by using three flash intensities: −25 dB (0.0087 cd·s/m2), 0 dB (2.75 cd·s/m2), and +5 dB (8.7 cd·s/m2). Next, photopic ERGs were acquired using a single flash protocol with a flash intensity of 3.0 cd·s/m2after 10 minutes of light adaptation.

Results

In scotopic ERG at 0.0087 cd·s/m2, mean b‐wave amplitude and peak time were 82.26 µV (SD ± 16.65 and 95% CI 68.33‐96.18) and 66.97 ms (SD ± 10.86 and 95% CI 57.90‐76.05), respectively. This flash intensity was below a‐wave threshold and resulted in b waves with greater peak times compared to those with higher intensities. At 2.75 cd·s/m2, the mean a‐wave amplitude and peak time were 53.95 µV (SD ± 11.63 and 95% CI 44.23‐63.67) and 16.13 ms (SD ± 2.62 and 95% CI 13.94‐18.31), and mean b‐wave amplitude and peak time were 119.57 µV (SD ± 15.54 and 95% CI 106.57‐132.56) and 32.00 ms (SD ± 6.47 and 95% CI 26.59‐37.41). At 8.7 cd·s/m2, the mean a‐wave amplitude and peak time were 58.85 µV (SD ± 14.90 and 95% CI 46.39‐71.31) and 15.59 ms (SD ± 2.63 and 95% CI 13.40‐17.79), and the mean b‐wave amplitude and peak time were 132.97 µV (SD ± 22.11 and 95% CI 114.48‐151.46) and 32.66 ms (SD ± 6.87 and 95% CI 26.91‐38.40).

In photopic ERG at 2.75 cd·s/m2, the mean a‐wave amplitude and peak time were 62.08 µV (SD ± 16.61 and 95% CI 48.19‐75.97) and 16.28 ms (SD ± 0.90 and 95% CI 15.53‐17.03), and the mean b‐wave amplitude and peak time were 214.93 µV (SD ± 70.41 and 95% CI 156.07‐273.80) and 33.09 ms (SD ± 1.27 and 95% CI 32.03‐34.15).

Conclusion

Using a portable ERG system with a brief ERG protocol to perform electroretinographies in wild giant pandas is a practical, useful, and reliable method for the rapid assessment of their retinal function.
Structured Methodology for Clustering Gas Turbine Transients by Means of Multivariate Time Series
Authors: Losi Enzo , Venturini Mauro , Manservigi Lucrezia , Ceschini Giuseppe Fabio , Bechini Giovanni , Cota Giuseppe , Riguzzi Fabrizio
Published: January 2021

At present, the challenges related to energy market force gas turbine owners to improve the reliability and availability of gas turbine engines, especially in the ever competitive Oil and Gas sector. Gas turbine trip leads to business interruption and also reduces equipment remaining useful life. Thus, the identification of symptoms of trips allows the prediction of their occurrence and avoids further damages and costs. Gas turbine transients are tracked by gas turbine operators while they occur, but a database including the complete details of past events for many fleets of engines is not always available. Therefore, a methodology aimed at classifying transients into clusters that identify the type of event (e.g., normal shutdown or trip) is required. Clustering is a data mining technique that addresses the scope of partitioning multivariate time series (MTS) into a given number of homogeneous and separated groups. Thus, the multivariate time series belonging to the same cluster are expected to be very similar to each other. This paper presents a structured methodology composed of a subsequent matching algorithm, a featured-based clustering approach exploiting the unsupervised fuzzy C-means algorithm and a procedure that assigns a label to each cluster for classification purposes. The methodology is applied to a real-word case-study that includes transients acquired from a fleet of Siemens gas turbines in operation during 3 years. The results obtained by using heterogeneous datasets including six measured variables allowed values of Precision, Recall and Accuracy higher than 90% in almost all cases.
The Data-Driven Surrogate Model-Based Dynamic Design of Aeroengine Fan Systems
Authors: Zhu Yun-Peng , Yuan Jie , Lang Z. Q. , Schwingshackl C. W. , Salles Loic , Kadirkamanathan V.
Published: January 2021

High-cycle fatigue failures of fan blade systems due to vibrational loads are of great concern in the design of aeroengines, where energy dissipation by the relative frictional motion in the dovetail joints provides the main damping to mitigate the vibrations. The performance of such a frictional damping can be enhanced by suitable coatings. However, the analysis and design of coated joint roots of gas turbine fan blades are computationally expensive due to strong contact friction nonlinearities and also complex physics involved in the dovetail. In this study, a data-driven surrogate model, known as the Nonlinear in Parameter AutoRegressive with eXegenous input (NP-ARX) model, is introduced to circumvent the difficulties in the analysis and design of fan systems. The NP-ARX model is a linear input–output model, where the model coefficients are nonlinear functions of the design parameters of interest, such that the Frequency Response Function (FRF) can be directly obtained and used in the system analysis and design. A simplified fan-bladed disc system is considered as the test case. The results show that using the data-driven surrogate model, an efficient and accurate design of aeroengine fan systems can be achieved. The approach is expected to be extended to solve the analysis and design problems of many other complex systems.
Bending Detection of Li-Ion Pouch Cells Using Impedance Spectra
Authors: Derakhshan Mohsen , Gilaki Mehdi , Stacy Andrew , Sahraei Elham , Soudbakhsh Damoon
Published: January 2021

Li-ion batteries are the preferred choice of energy storage in many applications. However, the potential for fire and explosion due to mechanical damage remains a safety concern. Currently, there are no criteria for the extent of the mechanical damage under which the batteries are safe to use. Here, we investigate the effects of bending damage to Li-ion cells on their impedance spectra. After the initial characterization of four Li-ion pouch cells, one of the cells underwent a three-point bending load. We measured the impedance spectra of this cell after each increment of loading. The impedance data of the control group cells were collected at the same intervals as the damaged cell. A distributed equivalent circuit model (dECM) was developed using the data from the electrochemical impedance spectroscopy (EIS) procedure. We observed that several model parameters such as the magnitude of constant phase elements had similar trends in the control cells and the bent cell. However, some model parameters such as resistances in parallel with constant phase elements, and the inductor showed dependency on the extent of the damage. These results suggest the potential for use of such parameters as an indicator of mechanical damage when visual inspection of cells is not possible in a battery pack setup. Future steps include investigation of similar trends for other commercial batteries and chemistries and form factors to verify the applicability of the current findings in a broader context.
Leveraging Task Modularity in Reinforcement Learning for Adaptable Industry 4.0 Automation
Authors: Chen Qiliang , Heydari Babak , Moghaddam Mohsen
Published: January 2021

The vision of Industry 4.0 is to materialize the notion of a lot-size of one through enhanced adaptability and resilience of manufacturing and logistics operations to dynamic changes or deviations on the shop floor. This article is motivated by the lack of formal methods for efficient transfer of knowledge across different yet interrelated tasks, with special reference to collaborative robotic operations such as material handling, machine tending, assembly, and inspection. We propose a meta reinforcement learning framework to enhance the adaptability of collaborative robots to new tasks through task modularization and efficient transfer of policies from previously learned task modules. Our experiments on the OpenAI Gym Robotics environments Reach, Push, and Pick-and-Place indicate an average 75% reduction in the number of iterations to achieve a 60% success rate as well as a 50%-80% improvement in task completion efficiency, compared to the deep deterministic policy gradient (DDPG) algorithm as a baseline. The significant improvements achieved in the jumpstart and asymptotic performance of the robot create new opportunities for investigating the current limitations of learning robots in industrial settings, associated with sample inefficiency and specialization on one task through modularization and transfer learning.
A Plate-Like Sensor for the Identification of Sample Viscoelastic Properties Using Contact Resonance Atomic Force Microscopy
Authors: Aureli Matteo , Tung Ryan
Published: January 2021

In this article, we present a new contact resonance atomic force microscopy-based method utilizing a square, plate-like microsensor to accurately estimate viscoelastic sample properties. A theoretical derivation, based on Rayleigh–Ritz method and on an “unconventional” generalized eigenvalue problem, is presented and a numerical experiment is devised to verify the method. We present an updated sensitivity criterion that allows users, given a set of measured in-contact eigenfrequencies and modal damping ratios, to select the best eigenfrequency for accurate data estimation. The verification results are then presented and discussed. Results show that the proposed method performs extremely well in the identification of viscoelastic properties over broad ranges of nondimensional sample stiffness and damping values.
Dynamic Electrochemical Impedance Spectroscopy of Lithium-ion Batteries: Revealing Underlying Physics through Efficient Joint Time-Frequency Modeling
Authors: Teo Linnette , Subramanian Venkat R. , Schwartz Daniel T.
Published: January 2021

The value and interpretation of dynamic electrochemical impedance spectroscopy (DEIS) during the charging and discharging of lithium-ion batteries is examined using the Doyle-Fuller-Newman pseudo-two-dimensional (P2D) lithium-ion battery model with parameters for a lithium-cobalt-oxide/graphite cell. Two computational approaches are explored to balance accuracy, speed, and interpretability: (i) A brute force time domain calculation of the full nonlinear equation set subject to direct current (DC) plus superimposed sinusoidal modulation of frequency ω
1, followed by post-processing with short-time Fourier transforms to track the dynamic impedance signal at the modulation frequency during charge and discharge; (ii) A fast-computing time-separated method that solves the C-rate dependent P2D equations for the DC charge/discharge transients occurring on the slow time-scales, t

b
∼ O(3600 s/C), followed by solutions to linearized frequency domain equations derived for direct computation of the dynamic impedance signal. The time-separated method is rigorously correct in the limit 1/(t

b

ω
1) → 0. Key physics that drives differences between stationary and dynamic EIS signals is easily explored with the time-separated method. C-rate dependent studies show that DEIS signals are selectively sensitive to interfacial processes in ways that may be promising for real-time diagnostics and control of the negative electrode at high states-of-charge (SOC) and the positive electrode at low SOCs.
Tea Polyphenol Attenuates Oxidative Stress‐Induced Degeneration of Intervertebral Discs by Regulating the Keap1/Nrf2/ARE Pathway
Authors: Song Dawei , Ge Jun , Wang Yingjie , Yan Qi , Wu Cenhao , Yu Hao , Yang Ming , Yang Huilin , Zou Jun
Published: January 2021

Objective. Intervertebral disc degeneration (IDD) and low back pain caused by IDD have attracted public attention owing to their extremely high incidence and disability rate. Oxidative stress is a major cause of IDD. Tea polyphenols (TP) are natural‐derived antioxidants extracted from tea leaves. This study explored the protective role of TP on the nucleus pulposus cells (NPCs) of intervertebral discs and their underlying mechanism. Methods. An in vitro model of H2O2‐induced degeneration of NPCs was established. RT‐qPCR and western blotting were used to detect the mRNA and protein expression of the targets. An in vivo model of IDD was established via acupuncture of the intervertebral disc. Radiological imaging and histological staining were performed to evaluate the protective role of TP. Results. H2O2 contributed to NPC degeneration by inducing high levels of oxidative stress. TP treatment effectively increased the expression of nucleus pulposus matrix‐associated genes and reduced the expression of degeneration factors. Further mechanistic studies showed that TP delayed H2O2‐mediated NPC degeneration by activating the Keap1/Nrf2/ARE pathway. In vivo experiments showed that TP delayed the degeneration of NPCs in rats through the Keap1/Nrf2/ARE pathway. Conclusion. Our study confirmed that TP activates the Keap1/Nrf2/ARE pathway to exert an antioxidative stress role, ultimately delaying the degeneration of intervertebral discs.
FBG‐Based Sensing for Structural Health Monitoring of Road Infrastructure
Authors: Braunfelds Janis , Senkans Ugis , Skels Peteris , Janeliukstis Rims , Salgals Toms , Redka Dmitrii , Lyashuk Ilya , Porins Jurgis , Spolitis Sandis , Haritonovs Viktors , Bobrovs Vjaceslavs
Published: January 2021

Public road infrastructure is developed all around the world. To save resources, ensure public safety, and provide longer‐lasting road infrastructure, structural health monitoring (SHM) applications for roads have to be researched and developed. Asphalt is one of the largest used surface materials for the road building industry. This material also provides relatively easy fiber optical sensor technology installment, which can be effectively used for SHM applications—road infrastructure monitoring as well as for resource optimization when road building or their repairs are planned. This article focuses on the research of the fiber Bragg grating (FBG) optical temperature and strain sensor applications in road SHM, which is part of the greater interdisciplinary research project started at the Riga Technical University in the year 2017. Experimental work described in this article was realized in one of the largest Latvian road sites where the FBG strain and temperature sensors were installed into asphalt pavement, and experiments were carried out in two main scenarios. Firstly, in a controlled environment with a calibrated falling weight deflectometer (FWD) to test the installed FBG sensors. Secondly, by evaluating the real‐time traffic impact on the measured strain and temperature, where different types of vehicles passed the asphalt span in which the sensors were embedded. The findings in this research illustrate that by gathering and combining data from calibrated FWD measurements, measurements from embedded FBG optical sensors which were providing the essential information of how the pavement structure could sustain the load and information about the traffic intensity on the specific road section, and the structural life of the pavement can be evaluated and predicted. Thus, it enables the optimal pavement future design for necessary requirements and constraints as well as efficient use, maintenance, and timely repairs of the public roads, directly contributing to the overall safety of our transportation system.
Antiangiogenic and Antitumor Therapy for Retinoblastoma with Hypoxia-Inducible Factor-1α siRNA and Celastrol Co-Delivery Nanomicelles
Authors: Yang Fan , Guo Zhihua , Shi Liuqi , Li Zhanrong , Zhang Junjie , Chai Chang , Li Jingguo
Published: January 2021

Retinoblastoma (RB) makes up about 3% of all childhood malignancies. Chemotherapy is commonly applied for RB treatment, while the clinical effectiveness varies significantly due to the cancer therapeutic resistances. Hypoxic tumor microenvironment, a hallmark of all tumors, is strongly
associated with malignant progress and therapeutic resistances. The hypoxia mainly promotes the angiogenesis by upregulating pro-angiogenetic pathways. In this work, polymeric micelles are used as the carrier to deliver celastrol and siRNA to RB cells for achieving synergistic anti-tumor and
antiangiogenesis effects. The micelle vectors have shown effective cellular internalization and release of loaded-celastrol and HIF-1 siRNA. The co-delivery system specifically and synergistically inhibits the expression of HIF-1α and VEGF in RB cells, suppresses the HIF-1α /VEGF/VEGFR
signaling pathway, and impedes the proliferation, migration, and invasion of vascular endothelial cells. The polymer micellar carrier that co-delivers HIF-1α siRNA and celastrol is used for antiangiogenic and antitumor therapy of RB. Altogether, the results show that our polymeric micelle
delivery system can be used to overcome barriers of drug resistance induced by angiogenesis and develop new drug/siRNA combinatory therapies.
The Physical Properties of Tripeptide Stereocomplex Nano-Formations
Authors: Nahhas Alaa F. , Nahhas Alrayan F. , Webster Thomas J.
Published: January 2021

The fast-growing use of supramolecular hydrogelators as biomaterials for a variety of applications, ranging from wound healing to drug delivery to tissue engineering, has highlighted the importance of synthetic design over recent years. Here, we report a new class of nanosheet stereocomplexes
in aqueous solution and at physiological conditions (i. e., pH7.4), which are formed by physically mixing right- and left-handed tripeptide supramolecular hydrogelators without any external stimulus. Such tripeptides were obtained by incorporating either α-aminoisobutyric acid (Aib,
U) or alanine (Ala, A) at the C-terminus or middle position of known peptide hydrogelators containing naphthalene and two phenylalanine residues. For hydrogels of these peptides, our results show that their morphologies and physical properties changed upon mixing with the L- and D-forms of
the peptides forming suspension stereocomplexes. These interactions reduced molecular mobility by forming new structures with new properties and, therefore, increased the thermal stability of the compound promising for numerous medical applications.
A Tenofovir-Loaded Glycyrrhetinic Acid-Modified Cationic Liposome for Targeted Therapy of Hepatitis B Virus
Authors: Yao Dongping , Liu Dongtao , Luo Ruijie , He Siyan , Bai Lang , Yang Yang , Ma Jialin , He Xi , Hu Mingxing , Luo Haozhong , Chen Bin , Liu Feng , Ye Tinghong , Song Xiangrong , Zhang Zhongwei , Xie Yongmei
Published: January 2021

Tenofovir (TFV), an acyclic nucleoside analog, exhibits potent anti-HBV activity. However, poor bioavailability, nephrotoxicity and bone toxicity limit its further clinical application. In this work, a novel tenofovir-loaded glycyrrhetinic acidmodified cationic liposome (TGCL) was prepared
for targeted therapy of HBV. The TGCL had an average particle size of 107.39 ± 1.21 nm and an entrapment efficiency of 89.83 ± 2.70% with a positive zeta potential of 37.63 ± 1.22 mV. The results of in vitro indicated that the inhibitory effects on HBsAg, HBeAg
and HBV cccDNA of TGCL in HepG2.2.15 cells were significantly better than that of free TFV and non-targeted cationic liposome. In the DHBV-infected duck model, TGCL showed remarkably suppression on DHBV DNA than that of free TFV. Overall, TGCL is a promising formulation of TFV for targeted
therapy of HBV.
Modulation of IL-6/STAT3 signaling axis in CD4+FOXP3− T cells represents a potential antitumor mechanism of azacitidine
Authors: Lamprianidou Eleftheria , Kordella Chryssoula , Kazachenka Anastasiya , Zoulia Emmanouela , Bernard Elsa , Filia Anastasia , Laidou Stamatia , Garantziotis Panayiotis , Vassilakopoulos Theodoros P. , Papageorgiou Sotirios G. , Pappa Vassiliki , Galanopoulos Athanasios G. , Viniou Nora , Nakou Evangelia , Kalafati Lydia , Chatzidimitriou Anastasia , Kassiotis George , Papaemmanuil Elli , Mitroulis Ioannis , Kotsianidis Ioannis
Published: January 2021

CD4+ T cells orchestrate immune responses and are actively engaged in shaping tumor immunity. Signal transducer and activator of transcription (STAT) signaling controls the epigenetic tuning of CD4+ T-cell differentiation and polarization, and perturbed STAT signaling networks in CD4+ T cells subvert antitumor immunity in malignancies. Azacitidine (AZA), the mainstay therapy for high-risk myelodysplastic syndromes (HR-MDS), affects CD4+ T-cell polarization and function, but whether this contributes to AZA efficacy is currently unknown. By using functional proteomic, transcriptomic, and mutational analyses in 73 HR-MDS patients undergoing AZA therapy, we demonstrate that responding patients exhibited a coordinated CD4+ T-cell immune response and downregulated the inflammatory cytokine signaling pathways in CD4+ T cells after AZA, in contrast to nonresponders who upregulated the same pathways. We further observed an AZA-mediated downregulation of intereukin-6 (IL-6)—induced STAT3 phosphorylation in CD4+FOXP3− conventional T cells (Tcons) that correlated independently with better response and survival, whereas it was also not associated with the mutation number and profile of the patients. The AZA-induced downregulation of IL-6/STAT3 axis in Tcons restored the STAT signaling architecture in CD4+ T-cell subsets, whereas STAT signaling networks remained disorganized in patients who upregulated IL-6/STAT3 activity in Tcons. Given the pivotal role of CD4+ T cells in adaptive immunity, our findings suggest that the downregulation of the IL-6/STAT3 pathway in Tcons potentially constitutes a previously unrecognized immune-mediated mechanism of action of AZA and sets the scene for developing rational strategies of AZA combinations with IL-6/STAT3 axis inhibitors.
Real-life experience with CPX-351 and impact on the outcome of high-risk AML patients: a multicentric French cohort
Authors: Chiche Edmond , Rahmé Ramy , Bertoli Sarah , Dumas Pierre-Yves , Micol Jean-Baptiste , Hicheri Yosr , Pasquier Florence , Peterlin Pierre , Chevallier Patrice , Thomas Xavier , Loschi Michael , Genthon Alexis , Legrand Ollivier , Mohty Mohamad , Raffoux Emmanuel , Auberger Patrick , Caulier Alexis , Joris Magalie , Bonmati Caroline , Roth-Guepin Gabrielle , Lejeune Caroline , Pigneux Arnaud , Vey Norbert , Recher Christian , Ades Lionel , Cluzeau Thomas
Published: January 2021

CPX-351 is a liposomal formulation of cytarabine and daunorubicin approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML). We retrospectively analyzed the efficacy and safety of CPX-351 in a real-world setting in 103 patients from 12 French centers, including the evaluation of molecular abnormalities at baseline and minimal residual disease (MRD) in responding patients, compared with a historical data set from Bordeaux-Toulouse DATAML registry. A favorable safety profile was observed, with a low frequency of alopecia (11%) and gastrointestinal toxicity (50%). The overall response rate after induction was 59%, and MRD <10−3 was achieved in 57% of complete response (CR)/CR with incomplete hematological recovery (CRi) patients. Only the presence of mutated TP53 (P = .02) or PTPN11 (P = .004) predicted lower response in multivariate analysis. Interestingly, high-risk molecular prognosis subgroups defined by 2017 European LeukemiaNet risk stratification, including ASXL1 and RUNX1 mutations, were not associated with a significantly lower response rate using CPX-351. With a median follow-up of 8.6 months, median overall survival (OS) was 16.1 months. Thirty-six patients underwent allogeneic stem cell transplantation with a significantly longer median OS compared with nontransplanted patients (P < .001). In multivariate analyses, only spliceosome mutations were associated with better OS (P = .04). In comparison with intensive chemotherapy, there was no difference in OS for patients <60 years. These data confirm the efficacy and safety of CPX-351 in high-risk AML (t-AML and MRC-AML) in a real-life setting. CPX-351 is a treatment of choice for patients aged ≥60 years.
COCONUT online: Collection of Open Natural Products database
Authors: Sorokina Maria , Merseburger Peter , Rajan Kohulan , Yirik Mehmet Aziz , Steinbeck Christoph
Published: January 2021

Natural products (NPs) are small molecules produced by living organisms with potential applications in pharmacology and other industries as many of them are bioactive. This potential raised great interest in NP research around the world and in different application fields, therefore, over the years a multiplication of generalistic and thematic NP databases has been observed. However, there is, at this moment, no online resource regrouping all known NPs in just one place, which would greatly simplify NPs research and allow computational screening and other in silico applications. In this manuscript we present the online version of the COlleCtion of Open Natural prodUcTs (COCONUT): an aggregated dataset of elucidated and predicted NPs collected from open sources and a web interface to browse, search and easily and quickly download NPs. COCONUT web is freely available at https://coconut.naturalproducts.net.
Profiling and analysis of chemical compounds using pointwise mutual information
Authors: Čmelo I. , Voršilák M. , Svozil D.
Published: January 2021

Pointwise mutual information (PMI) is a measure of association used in information theory. In this paper, PMI is used to characterize several publicly available databases (DrugBank, ChEMBL, PubChem and ZINC) in terms of association strength between compound structural features resulting in database PMI interrelation profiles. As structural features, substructure fragments obtained by coding individual compounds as MACCS, PubChemKey and ECFP fingerprints are used. The analysis of publicly available databases reveals, in accord with other studies, unusual properties of DrugBank compounds which further confirms the validity of PMI profiling approach. Z-standardized relative feature tightness (ZRFT), a PMI-derived measure that quantifies how well the given compound’s feature combinations fit these in a particular compound set, is applied for the analysis of compound synthetic accessibility (SA), as well as for the classification of compounds as easy (ES) and hard (HS) to synthesize. ZRFT value distributions are compared with these of SYBA and SAScore. The analysis of ZRFT values of structurally complex compounds in the SAVI database reveals oligopeptide structures that are mispredicted by SAScore as HS, while correctly predicted by ZRFT and SYBA as ES. Compared to SAScore, SYBA and random forest, ZRFT predictions are less accurate, though by a narrow margin (AccZRFT = 94.5%, AccSYBA = 98.8%, AccSAScore = 99.0%, AccRF = 97.3%). However, ZRFT ability to distinguish between ES and HS compounds is surprisingly high considering that while SYBA, SAScore and random forest are dedicated SA models, ZRFT is a generic measurement that merely quantifies the strength of interrelations between structural feature pairs. The results presented in the current work indicate that structural feature co-occurrence, quantified by PMI or ZRFT, contains a significant amount of information relevant to physico-chemical properties of organic compounds.
Dietary branched-chain amino acid assessment in broilers from 22 to 35 days of age
Authors: Kidd M. T. , Poernama F. , Wibowo T. , Maynard C. W. , Liu S. Y.
Published: January 2021

Background

Valine and isoleucine are similar in chemical structure and their limitation in broiler chicken diets. To evaluate their limitation and interactive effects, multivariate assessment nutrition studies for the branched-chain amino acids (BCAA) are needed. A three level (− 1, 0, + 1), three-factor Box-Behnken design study was conducted to assess dietary BCAA ratios to lysine of 65, 75, and 85 for valine, 58, 66, and 74 for isoleucine, and 110, 130, and 150 for leucine in male and female Lohman Indian River broilers from 22 to 35 d of age.

Results

Live performance of male broilers was not affected by BCAA level. However, male broilers fed increasing isoleucine had improved (P = 0.07) carcass yield as leucine and valine were reduced. Female broilers had improved body weight gain (P = 0.05) and feed conversion (P = 0.003) when leucine and isoleucine were at their lowest levels, independent of valine, but increasing leucine impaired live performance and warranted concomitant increases in isoleucine to restore responses. Increasing dietary isoleucine and valine in female broilers increased breast meat yield (P = 0.05), but increasing leucine tended to diminish the response.

Conclusion

The female Lohman Indian River broiler is more sensitive to BCAA diet manipulation than males. Specifically, as dietary leucine is increased in female broilers, dietary isoleucine increases were needed to offset the negative effects. Both increases in dietary valine and isoleucine improved breast meat yield in female broilers, but only when birds were fed the lowest dietary leucine.
PEO based polymer-ceramic hybrid solid electrolytes: a review
Authors: Feng Jingnan , Wang Li , Chen Yijun , Wang Peiyu , Zhang Hanrui , He Xiangming
Published: January 2021

Compared with traditional lead-acid batteries, nickel–cadmium batteries and nickel-hydrogen batteries, lithium-ion batteries (LIBs) are much more environmentally friendly and much higher energy density. Besides, LIBs own the characteristics of no memory effect, high charging and discharging rate, long cycle life and high energy conversion rate. Therefore, LIBs have been widely considered as the most promising power source for mobile devices. Commonly used LIBs contain carbonate based liquid electrolytes. Such electrolytes own high ionic conductivity and excellent wetting ability. However, the use of highly flammable and volatile organic solvents in them may lead to problems like leakage, thermo runaway and parasitic interface reactions, which limit their application. Solid polymer electrolytes (SPEs) can solve these problems, while they also bring new challenges such as poor interfacial contact with electrodes and low ionic conductivity at room temperature. Many approaches have been tried to solve these problems. This article is divided into three parts to introduce polyethylene oxide (PEO) based polymer-ceramic hybrid solid electrolyte, which is one of the most efficient way to improve the performance of SPEs. The first part focuses on polymer-lithium salt (LiX) matrices, including their ionic conduction mechanism and impact factors for their ionic conductivity. In the second part, the influence of both active and passive ceramic fillers on SPEs are reviewed. In the third part, composite SPEs’ preparation methods, including solvent casting and thermocompression, are introduced and compared. Finally, we propose five key points on how to make composite SPEs with high ionic conductivity for reference.
Fungi against insects and contrariwise as biological control models
Authors: Elkhateeb Waill A. , Mousa Kareem M. , ELnahas Marwa O. , Daba Ghoson M.
Published: January 2021

Background

Biological control of insects is the current goal of modern researches to avoid using the harmful chemicals. Some fungi are capable of infecting and killing insects and, hence, are commonly known as entomopathogenic fungi (EPF). On the other hand, some insects can kill harmful fungal strains using their products such as peptides. Hence, the aim of this review article is to highlight the use of EPF as biocontrol tools against each other.

Results

EPF are generally characterized by having a wide range of hosts which made them the perfect candidate for biological control missions. They are existing in abundance in the environment and involved in plenty of environmental interactions. They have prestigious enzymatic machinery and toxins that contribute as killing tools. Moreover, after penetrating the insect, the expanded vegetative growth of hyphal bodies enabling the invasion of the fungi throughout the entire tissues of host insect cause physic, histolytic, and pathologic changes ultimately leading to the death of the host insect. On the other hand, some insects can kill harmful fungal strains using their secreted products such as peptides.

Conclusion

In this review, the use of fungi and insects as biological control agents against each other was described. Furthermore, the history of using EPF for this purpose, their killing mechanism, host range, and the factors affecting EPF virulence were highlighted. Moreover, the role of insect’s immunology and some insect’s products as antifungal agents was presented focusing on peptides with biological activities against fungi. Finally, future prospects concerning the use of insects and fungi in biological control process were discussed.
Adrenomedullin-RAMP2 and -RAMP3 Systems Regulate Cardiac Homeostasis during Cardiovascular Stress
Authors: Cui Nanqi , Sakurai Takayuki , Kamiyoshi Akiko , Ichikawa-Shindo Yuka , Kawate Hisaka , Tanaka Megumu , Tanaka Masaaki , Wei Yangxuan , Kakihara Shinji , Zhao Yunlu , Aruga Kohsuke , Kawagishi Hiroyuki , Nakada Tsutomu , Yamada Mitsuhiko , Shindo Takayuki
Published: January 2021

Adrenomedullin (AM) is a peptide hormone with multiple physiological functions, which are regulated by its receptor activity–modifying proteins, RAMP2 and RAMP3. We previously reported that AM or RAMP2 knockout (KO) (AM–/–, RAMP2–/–) is embryonically lethal in mice, whereas RAMP3–/– mice are apparently normal. AM, RAMP2, and RAMP3 are all highly expressed in the heart; however, their functions there are not fully understood. Here, we analyzed the pathophysiological functions of the AM-RAMP2 and AM-RAMP3 systems in hearts subjected to cardiovascular stress. Cardiomyocyte-specific RAMP2–/– (C-RAMP2–/–) and RAMP3–/– showed no apparent heart failure at base line. After 1 week of transverse aortic constriction (TAC), however, C-RAMP2–/– exhibited significant cardiac hypertrophy, decreased ejection fraction, and increased fibrosis compared with wild-type mice. Both dP/dtmax and dP/dtmin were significantly reduced in C-RAMP2–/–, indicating reduced ventricular contractility and relaxation. Exposing C-RAMP2–/– cardiomyocytes to isoproterenol enhanced their hypertrophy and oxidative stress compared with wild-type cells. C-RAMP2–/– cardiomyocytes also contained fewer viable mitochondria and showed reduced mitochondrial membrane potential and respiratory capacity. RAMP3–/– also showed reduced systolic function and enhanced fibrosis after TAC, but those only became apparent after 4 weeks. A reduction in cardiac lymphatic vessels was the characteristic feature in RAMP3–/–. These observations indicate the AM-RAMP2 system is necessary for early adaptation to cardiovascular stress through regulation of cardiac mitochondria. AM-RAMP3 is necessary for later adaptation through regulation of lymphatic vessels. The AM-RAMP2 and AM-RAMP3 systems thus play separate critical roles in the maintenance of cardiovascular homeostasis against cardiovascular stress.