bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and Validation of a Hypoxia-Associated Prognostic Signature Related to Osteosarcoma Metastasis and Immune Infiltration
Authors: Fu Yucheng , Bao Qiyuan , Liu Zhuochao , He Guoyu , Wen Junxiang , Liu Qi , Xu Yiqi , Jin Zhijian , Zhang Weibin
Published: March 2021

Background

Increasing evidence has shown that hypoxia microenvironment relates to tumor initiation and progression. However, no studies focus on the application of hypoxia-associated genes in predicting osteosarcoma patients’ prognosis. This research aims to identify the hypoxia-associated genes related to osteosarcoma metastasis and construct a gene signature to predict osteosarcoma prognosis.

Methods

The differentially expressed messenger RNAs (DEmRNAs) related to osteosarcoma metastasis were identified from Therapeutically Applicable Research to Generate Effective Treatments (Target) database. Univariate and multivariate cox regression analyses were performed to develop the hypoxia-associated prognostic signature. The Kaplan–Meier (KM) survival analyses of patients with high and low hypoxia risk scores were conducted. The nomogram was constructed and the gene signature was validated in the external Gene Expression Omnibus (GEO) cohort. Single-sample gene set enrichment analysis (ssGSEA) was conducted to investigate the relationships between immune infiltration and gene signature.

Results

Two genes, including decorin (DCN) and prolyl 4-hydroxylase subunit alpha 1 (P4HA1), were involved in the hypoxia-associated gene signature. In training and testing datasets, patients with high-risk scores showed lower survival rates and the gene signature was identified as the independent prognostic factor. Receiver operating characteristic (ROC) curves demonstrated the robustness of signature. Functional analyses of DEmRNAs among high- and low-risk groups revealed that immune-associated functions and pathways were significantly enriched. Furthermore, ssGSEA showed that five immune cells (DCs, macrophages, neutrophils, pDCs, and TIL) and three immune features (CCR, APC co inhibition, and Check-point) were down-regulated in the high-risk group.

Conclusion

The current study established and validated a novel hypoxia-associated gene signature in osteosarcoma. It could act as a prognostic biomarker and serve as therapeutic guidance in clinical applications.
The Role of miR-31-5p in the Development of Intervertebral Disc Degeneration and Its Therapeutic Potential
Authors: Zhou Yong , Deng Mingsi , Su Jiqing , Zhang Wei , Liu Dongbiao , Wang Zhengguang
Published: March 2021

Intervertebral disc degeneration (IDD) refers to the abnormal response of cell-mediated progressive structural failure. In order to understand the molecular mechanism of the maintenance and destruction of the intervertebral disc, new IDD treatment methods are developed. Here, we first analyzed the key regulators of IDD through microRNAs microarrays. Then, the level of miR-31-5p was evaluated by qRT-PCR. The association between miR-31-5p and Stromal cell-derived factor 1 (SDF-1)/CXCR7 axis was assessed by 3′-untranslated region (UTR) cloning and luciferase assay. The apoptosis of cells under different treatments was evaluated by flow cytometer. The cell proliferation was assessed by EdU assay. After IDD model establishment, the discs of mice tail were harvested for histological and radiographic evaluation in each group. Finally, the protein levels of SDF-1, CXCR7, ADAMTS-5, Col II, Aggrecan, and MMP13 were assessed by western blot. The results show that miR-31-5p is a key regulator of IDD and its level is down-regulated in IDD. Overexpression of miR-31-5p facilitates nucleus pulposus cell proliferation, inhibits apoptosis, facilitates ECM formation, and inhibits the level of matrix degrading enzymes in NP cells. The SDF-1/CXCR7 axis is the direct target of miR-31-5p. miR-31-5p acts on IDD by regulating SDF-1/CXCR7. In vitro experiments further verified that the up-regulation of miR-31-5p prevented the development of IDD. In conclusion, overexpression of miR-31-5p can inhibit IDD by regulating SDF-1/CXCR7.
Strength Through Unity: The Power of the Mega-Scaffold MACF1
Authors: Cusseddu Rebecca , Robert Amélie , Côté Jean-François
Published: March 2021

The tight coordination of diverse cytoskeleton elements is required to support several dynamic cellular processes involved in development and tissue homeostasis. The spectraplakin-family of proteins are composed of multiple domains that provide versatility to connect different components of the cytoskeleton, including the actin microfilaments, microtubules and intermediates filaments. Spectraplakins act as orchestrators of precise cytoskeletal dynamic events. In this review, we focus on the prototypical spectraplakin MACF1, a protein scaffold of more than 700 kDa that coordinates the crosstalk between actin microfilaments and microtubules to support cell-cell connections, cell polarity, vesicular transport, proliferation, and cell migration. We will review over two decades of research aimed at understanding the molecular, physiological and pathological roles of MACF1, with a focus on its roles in developmental and cancer. A deeper understanding of MACF1 is currently limited by technical challenges associated to the study of such a large protein and we discuss ideas to advance the field.
Exosomes and Obesity-Related Insulin Resistance
Authors: Lei Li-Min , Lin Xiao , Xu Feng , Shan Su-Kang , Guo Bei , Li Fu-Xing-Zi , Zheng Ming-Hui , Wang Yi , Xu Qiu-Shuang , Yuan Ling-Qing
Published: March 2021

Exosomes are extracellular vesicles, delivering signal molecules from donor cells to recipient cells. The cargo of exosomes, including proteins, DNA and RNA, can target the recipient tissues and organs, which have an important role in disease development. Insulin resistance is a kind of pathological state, which is important in the pathogeneses of type 2 diabetes mellitus (T2DM), gestational diabetes mellitus and Alzheimer’s disease. Furthermore, obesity is a kind of inducement of insulin resistance. In this review, we summarized recent research advances on exosomes and insulin resistance, especially focusing on obesity-related insulin resistance. These studies suggest that exosomes have great importance in the development of insulin resistance in obesity and have great potential for use in the diagnosis and therapy of insulin resistance.
Diethyl Malonate-Based Turn-On Chemical Probe for Detecting Hydrazine and Its Bio-Imaging and Environmental Applications With Large Stokes Shift
Authors: Qu Jianbo , Zhang Zhi-Hao , Zhang Haitao , Weng Zhen-Tao , Wang Jian-Yong
Published: March 2021

Diethyl malonate-based fluorescent probe NE-N2H4 was constructed for monitoring hydrazine (N2H4). The novel probe NE-N2H4 exhibits good properties, such as large Stokes shift (about 125 nm), good selectivity, and low cytotoxicity. This sensing probe NE-N2H4 can be operated to detect hydrazine in living HeLa cells. Especially after soaking in probe solution, the thin-layer chromatography (TLC) plate could detect the vapor of hydrazine. Therefore, the probe NE-N2H4 might be used to monitor hydrazine in biosamples and environmental problem.
Responsive Plasmonic Nanomaterials for Advanced Cancer Diagnostics
Authors: Lu Rong , Ni Jiankun , Yin Shengnan , Ji Yiding
Published: March 2021

Plasmonic nanostructures, particularly of noble-metal Au and Ag, have attracted long-lasting research interests because of their intriguing physical and chemical properties. Under light excitation, their conduction electrons can form collective oscillation with the electromagnetic fields at particular wavelength, leading to localized surface plasmon resonance (LSPR). The remarkable characteristic of LSPR is the absorption and scattering of light at the resonant wavelength and greatly enhanced electric fields in localized areas. In response to the chemical and physical changes, these optical properties of plasmonic nanostructures will exhibit drastic color changes and highly sensitive peak shifts, which has been extensively used for biological imaging and disease treatments. In this mini review, we aim to briefly summarize recent progress of preparing responsive plasmonic nanostructures for biodiagnostics, with specific focus on cancer imaging and treatment. We start with typical synthetic approaches to various plasmonic nanostructures and elucidate practical strategies and working mechanism in tuning their LSPR properties. Current achievements in using responsive plasmonic nanostructures for advanced cancer diagnostics will be further discussed. Concise perspectives on existing challenges in developing plasmonic platforms for clinic diagnostics is also provided at the end of this review.
Dengue Virus Non-Structural Protein 5 as a Versatile, Multi-Functional Effector in Host–Pathogen Interactions
Authors: Bhatnagar Priya , Sreekanth Gopinathan Pillai , Murali-Krishna Kaja , Chandele Anmol , Sitaraman Ramakrishnan
Published: March 2021

Dengue is emerging as one of the most prevalent mosquito-borne viral diseases of humans. The 11kb RNA genome of the dengue virus encodes three structural proteins (envelope, pre-membrane, capsid) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5), all of which are translated as a single polyprotein that is subsequently cleaved by viral and host cellular proteases at specific sites. Non-structural protein 5 (NS5) is the largest of the non-structural proteins, functioning as both an RNA-dependent RNA polymerase (RdRp) that replicates the viral RNA and an RNA methyltransferase enzyme (MTase) that protects the viral genome by RNA capping, facilitating polyprotein translation. Within the human host, NS5 interacts with several proteins such as those in the JAK-STAT pathway, thereby interfering with anti-viral interferon signalling. This mini-review presents annotated, consolidated lists of known and potential NS5 interactors in the human host as determined by experimental and computational approaches respectively. The most significant protein interactors and the biological pathways they participate in are also highlighted and their implications discussed, along with the specific serotype of dengue virus as appropriate. This information can potentially stimulate and inform further research efforts towards providing an integrative understanding of the mechanisms by which NS5 manipulates the human-virus interface in general and the innate and adaptive immune responses in particular.
N-Acyl Homoserine Lactone-Mediated Quorum Sensing Regulates Species Interactions in Multispecies Biofilm Communities
Authors: Subramoni Sujatha , Muzaki Muhammad Zulfadhly Bin Mohammad , Booth Sean C. M. , Kjelleberg Staffan , Rice Scott A.
Published: March 2021

Bacterial biofilms are important medically, environmentally and industrially and there is a need to understand the processes that govern functional synergy and dynamics of species within biofilm communities. Here, we have used a model, mixed-species biofilm community comprised of Pseudomonas aeruginosa PAO1, Pseudomonas protegens Pf-5 and Klebsiella pneumoniae KP1. This biofilm community displays higher biomass and increased resilience to antimicrobial stress conditions such as sodium dodecyl sulfate and tobramycin, compared to monospecies biofilm populations. P. aeruginosa is present at low proportions in the community and yet, it plays a critical role in community function, suggesting it acts as a keystone species in this community. To determine the factors that regulate community composition, we focused on P. aeruginosa because of its pronounced impact on community structure and function. Specifically, we evaluated the role of the N-acyl homoserine lactone (AHL) dependent quorum sensing (QS) system of P. aeruginosa PAO1, which regulates group behaviors including biofilm formation and the production of effector molecules. We found that mixed species biofilms containing P. aeruginosa QS mutants had significantly altered proportions of K. pneumoniae and P. protegens populations compared to mixed species biofilms with the wild type P. aeruginosa. Similarly, inactivation of QS effector genes, e.g. rhlA and pvdR, also governed the relative species proportions. While the absence of QS did not alter the proportions of the two species in dual species biofilms of P. aeruginosa and K. pneumoniae, it resulted in significantly lower proportions of P. aeruginosa in dual species biofilms with P. protegens. These observations suggest that QS plays an important role in modulating community biofilm structure and physiology and affects interspecific interactions.
Extracellular Vesicles: Schistosomal Long-Range Precise Weapon to Manipulate the Immune Response
Authors: Avni Dror , Avni Orly
Published: March 2021

Schistosomiasis (Bilharziasis), a neglected tropical disease that affects more than 240 million people around the world, is caused by infection with the helminth parasiteSchistosoma. As part of their secretome, schistosomes release extracellular vesicles (EVs) that modulate the host immune response. The EV-harbored miRNAs upregulate the innate immune response of the M1 pathway and downregulate the differentiation toward the adaptive Th2 immunity. A schistosomal egg-derived miRNA increases the percentage of regulatory T cells. This schistosomal-inducible immunoediting process generates ultimately a parasitic friendly environment that is applied carefully as restrained Th2 response is crucial for the host survival and successful excretion of the eggs. Evidence indicates a selective targeting of schistosomal EVs, however, the underlying mechanisms are unclear yet. The effects of the schistosomes on the host immune system is in accordance with the hygiene hypothesis, attributing the dramatic increase in recent decades in allergy and other diseases associated with imbalanced immune response, to the reduced exposure to infectious agents that co-evolved with humans during evolution. Deciphering the bioactive cargo, function, and selective targeting of the parasite-secreted EVs may facilitate the development of novel tools for diagnostics and delivered therapy to schistosomiasis, as well as to immune-associated disorders.
Alkalinization Scenarios in the Mediterranean Sea for Efficient Removal of Atmospheric CO2 and the Mitigation of Ocean Acidification
Authors: Butenschön Momme , Lovato Tomas , Masina Simona , Caserini Stefano , Grosso Mario
Published: March 2021

It is now widely recognized that in order to reach the target of limiting global warming to well below 2°C above pre-industrial levels (as the objective of the Paris agreement), cutting the carbon emissions even at an unprecedented pace will not be sufficient, but there is the need for development and implementation of active Carbon Dioxide Removal (CDR) strategies. Among the CDR strategies that currently exist, relatively few studies have assessed the mitigation capacity of ocean-based Negative Emission Technologies (NET) and the feasibility of their implementation on a larger scale to support efficient implementation strategies of CDR. This study investigates the case of ocean alkalinization, which has the additional potential of contrasting the ongoing acidification resulting from increased uptake of atmospheric CO2 by the seas. More specifically, we present an analysis of marine alkalinization applied to the Mediterranean Sea taking into consideration the regional characteristics of the basin. Rather than using idealized spatially homogenous scenarios of alkalinization as done in previous studies, which are practically hard to implement, we use a set of numerical simulations of alkalinization based on current shipping routes to quantitatively assess the alkalinization efficiency via a coupled physical-biogeochemical model (NEMO-BFM) for the Mediterranean Sea at 1/16° horizontal resolution (~6 km) under an RCP4.5 scenario over the next decades. Simulations suggest the potential of nearly doubling the carbon-dioxide uptake rate of the Mediterranean Sea after 30 years of alkalinization, and of neutralizing the mean surface acidification trend of the baseline scenario without alkalinization over the same time span. These levels are achieved via two different alkalinization strategies that are technically feasible using the current network of cargo and tanker ships: a first approach applying annual discharge of 200 Mt Ca(OH)2 constant over the alkalinization period and a second approach with gradually increasing discharge proportional to the surface pH trend of the baseline scenario, reaching similar amounts of annual discharge by the end of the alkalinization period. We demonstrate that the latter approach allows to stabilize the mean surface pH at present day values and substantially increase the potential to counteract acidification relative to the alkalinity added, while the carbon uptake efficiency (mole of CO2 absorbed by the ocean per mole of alkalinity added) is only marginally reduced. Nevertheless, significant local alterations of the surface pH persist, calling for an investigation of the physiological and ecological implications of the extent of these alterations to the carbonate system in the short to medium term in order to support a safe, sustainable application of this CDR implementation.
The Effects of Tai Chi Exercise Among Adults With Chronic Heart Failure: An Overview of Systematic Review and Meta-Analysis
Authors: Huang Jinke , Qin Xiaohui , Shen Min , Xu Yanjuan , Huang Yong
Published: March 2021

Background: Tai chi (TC) is a popular form of exercise among adults with chronic heart failure (CHF), yet services are greatly underutilized. The aim of the current study was to identify and summarize the existing evidence and to systematically determine the clinical effectiveness of Tai Chi in the management of CHF using a systematic overview.

Methods: Both English and Chinese databases were searched for systematic reviews (SRs)/meta-analyses (MAs) on TC for CHF from their inception to June 2020. The methodological quality, reporting quality, and risk of bias of SRs/MAs were assessed using Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR-2), the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, and Risk of Bias in Systematic reviews (ROBIS), respectively. The evidence quality of outcome measures was assessed by the Grades of Recommendations, Assessment, Development and Evaluation (GRADE).

Results: Six SRs/MAs using a quantitative synthesis to assess various outcomes of TC in CHF were included in this overview. The methodological quality, reporting quality and risk of bias of the SRs/MAs and the evidence quality of the outcome measures are generally unsatisfactory. The limitations of the past SRs/MAs included the lack of either the protocol or registration, the list of excluded studies, and the computational details of meta-analysis were inadequately reported. The critical problems were that qualitative data synthesis relied on trials with small sample sizes and critical low quality.

Conclusions: TC may be a promising complementary treatment for CHF. However, further rigorous and comprehensive SRs/MAs and RCTs are required to provide robust evidence for definitive conclusions.
Angiotensinogen and the Modulation of Blood Pressure
Authors: Shu Zimei , Wan Jiahui , Read Randy J. , Carrell Robin W. , Zhou Aiwu
Published: March 2021

The angiotensin peptides that control blood pressure are released from the non-inhibitory plasma serpin, angiotensinogen, on cleavage of its extended N-terminal tail by the specific aspartyl-protease, renin. Angiotensinogen had previously been assumed to be a passive substrate, but we describe here how recent studies reveal an inherent conformational mechanism that is critical to the cleavage and release of the angiotensin peptides and consequently to the control of blood pressure. A series of crystallographic structures of angiotensinogen and its derivative forms, together with its complexes with renin show in molecular detail how the interaction with renin triggers a profound shift of the amino-terminal tail of angiotensinogen with modulation occurring at several levels. The tail of angiotensinogen is restrained by a labile disulfide bond, with changes in its redox status affecting angiotensin release, as demonstrably so in the hypertensive complication of pregnancy, pre-eclampsia. The shift of the tail also enhances the binding of renin through a tail-in-mouth allosteric mechanism. The N-terminus is now seen to insert into a pocket equivalent to the hormone-binding site on other serpins, with helix H of angiotensinogen unwinding to form key interactions with renin. The findings explain the precise species specificity of the interaction with renin and with variant carbohydrate linkages. Overall, the studies provide new insights into the physiological regulation of angiotensin release, with an ability to respond to local tissue and temperature changes, and with the opening of strategies for the development of novel agents for the treatment of hypertension.
Enrichment of Platinum Group Elements in Lower Cambrian Polymetallic Black Shale, SE Yangtze Block, China
Authors: Fu Yong , Yang Zhen , Li Chao , Xia Peng
Published: March 2021

Platinum group elements (PGEs) occur mainly in basic–ultrabasic igneous rocks and are concentrated by the differentiation and crystallization of magma. Thin polymetallic layers including Ni, Mo, V, PGEs, and rare-earth elements are widely developed in lower Cambrian black shales in southern China. The PGE contents in such layers may not be economically significant but are still unusually enriched. PGE enrichment mechanisms have not been widely studied, but here the PGE compositions of polymetallic layers in the Shuidong (Nayong) and Niuchang (Weng’an) sections of the SE Yangtze block in China were determined, and results compared with published data for the region. Results indicate that PGEs are enriched in the polymetallic layers, whereas the surrounding country rocks are barren. The ΣPGE contents in the Shuidong Ni–Mo deposits are generally lower than in the Niuchang V deposits. PGE distribution patterns in the polymetallic layers are similar to those in basic–ultrabasic rocks, indicating that such rocks played a role in the PGE enrichment. Oceanic hypoxia during the Sinian–Cambrian transition resulted in the production of large amounts of organic matter and H2S in the ocean. When high-salinity brine reached the ocean bottom, rapid changes in Eh–pH conditions caused enrichment of metals at the sediment–seawater interface, and this enrichment was later enhanced during diagenesis.
Sphingolipids as a Culprit of Mitochondrial Dysfunction in Insulin Resistance and Type 2 Diabetes
Authors: Roszczyc-Owsiejczuk Kamila , Zabielski Piotr
Published: March 2021

Insulin resistance is defined as a complex pathological condition of abnormal cellular and metabolic response to insulin. Obesity and consumption of high-fat diet lead to ectopic accumulation of bioactive lipids in insulin-sensitive tissues. Intracellular lipid accumulation is regarded as one of the major factors in the induction of insulin resistance and type 2 diabetes (T2D). A significant number of studies have described the involvement of ceramides and other sphingolipids in the inhibition of insulin-signaling pathway in both skeletal muscles and the liver. Adverse effects of sphingolipid accumulation have recently been linked to the activation of protein kinase Cζ (PKCζ) and protein phosphatase 2A (PP2A), which, in turn, negatively affect phosphorylation of serine/threonine kinase Akt [also known as protein kinase B (PKB)], leading to decreased glucose uptake in skeletal muscles as well as increased gluconeogenesis and glycogenolysis in the liver. Sphingolipids, in addition to their direct impact on the insulin signaling pathway, may be responsible for other negative aspects of diabetes, namely mitochondrial dysfunction and deficiency. Mitochondrial health, which is characterized by appropriate mitochondrial quantity, oxidative capacity, controlled oxidative stress, undisturbed respiratory chain function, adenosine triphosphate (ATP) production and mitochondrial proliferation through fission and fusion, is impaired in the skeletal muscles and liver of T2D subjects. Recent findings suggest that impaired mitochondrial function may play a key role in the development of insulin resistance. Mitochondria stay in contact with the endoplasmic reticulum (ER), Golgi membranes and mitochondria-associated membranes (MAM) that are the main places of sphingolipid synthesis. Moreover, mitochondria are capable of synthesizing ceramide though ceramide synthase (CerS) activity. Recently, ceramides have been demonstrated to negatively affect mitochondrial respiratory chain function and fission/fusion activity, which is also a hallmark of T2D. Despite a significant correlation between sphingolipids, mitochondrial dysfunction, insulin resistance and T2D, this subject has not received much attention compared to the direct effect of sphingolipids on the insulin signaling pathway. In this review, we focus on the current state of scientific knowledge regarding the involvement of sphingolipids in the induction of insulin resistance by inhibiting mitochondrial function.
Astrocyte Clocks and Glucose Homeostasis
Authors: Barca-Mayo Olga , López Miguel
Published: March 2021

The endogenous timekeeping system evolved to anticipate the time of the day through the 24 hours cycle of the Earth’s rotation. In mammals, the circadian clock governs rhythmic physiological and behavioral processes, including the daily oscillation in glucose metabolism, food intake, energy expenditure, and whole-body insulin sensitivity. The results from a series of studies have demonstrated that environmental or genetic alterations of the circadian cycle in humans and rodents are strongly associated with metabolic diseases such as obesity and type 2 diabetes. Emerging evidence suggests that astrocyte clocks have a crucial role in regulating molecular, physiological, and behavioral circadian rhythms such as glucose metabolism and insulin sensitivity. Given the concurrent high prevalence of type 2 diabetes and circadian disruption, understanding the mechanisms underlying glucose homeostasis regulation by the circadian clock and its dysregulation may improve glycemic control. In this review, we summarize the current knowledge on the tight interconnection between the timekeeping system, glucose homeostasis, and insulin sensitivity. We focus specifically on the involvement of astrocyte clocks, at the organism, cellular, and molecular levels, in the regulation of glucose metabolism.
Emulsion Characterization of the Heavy Oil-Alkaline Water System in Alkaline Flooding Mechanism Investigation Using a Combination of Modified Bottle Test and Sandpack Flooding
Authors: Xi Zhiyu , Jia Na , Shirif Ezeddin
Published: March 2021

Due to the diversity of alkali categories and reservoir conditions, the varied oil recovery driving mechanism of alkaline flooding is subjected to different types of emulsion generation. In this study, a modified bottle test method that assesses major emulsion type formation for preliminary prediction of alkaline flooding performance in oil recovery is introduced. The modified method considers the necessary energy input required for mixing immiscible bulk phases at low interfacial tension (IFT) regions to improve the representativity of emulsion formation in the bottle test to that of in porous media. To accurately evaluate the emulsion type and phase volume distribution from the bottle test, each emulsion phase after aging in the test bottle was sampled and its water content was measured through Karl Fischer titration. Afterward, material balance calculations other than pure volume observation were applied to quantify the emulsion volume and determine the major emulsion type formation. It is found that the majority of emulsion effluent type from the sandpack flooding test were in agreement with the bottle test forecast which proved the feasibility of the modified bottle test method. The statistically optimized experimental designs were implemented due to the simplicity of the new bottle test method and it considerably cut the time expense regarding the alkaline flooding performance prediction. The high versatility of the modified bottle test ensures that the alkali usage is not limited to the inorganic alkalis mentioned in this study; other type of alkaline solutions can also be used for further expanding the scope of its application.
Development of an Intelligent Power Management System for Solar PV-Wind-Battery-Fuel-Cell Integrated System
Authors: Ani Vincent Anayochukwu
Published: March 2021

The objective of this work is to develop a power management system that will control the power flow of an integrated renewable energy system with the focus on solar energy and wind energy and dual energy storage systems (batteries are used as the primary energy storage system for short to moderate storage term, whereas hydrogen fuel cell is used as a backup and long-term energy storage). These storage systems are needed to provide high reliability and control systems are necessary for the stable and optimal operation of the whole system. An Intelligent Power Management System (IPMS) is developed to handle various changes in power supply and power demand by managing erratic power and provide suitable control algorithm for the whole system. In order to test and validate the proposed IPMS model, simulations were conducted under various power supply and power demand using power system modeled in HOMER environment. The performed simulations confirm the ability of the IPMS to satisfy the load at all times using solar and wind power (which are unsteady renewables), through the support of batteries and hydrogen fuel cell without a reduction in the power quality or load supply.
The Effects of Subsidy Policy on Electric Vehicles and the Supporting Regulatory Policies: Evidence From Micro Data of Chinese Mobile Manufacturers
Authors: Liu Xiang-Feng , Wang Ling
Published: March 2021

Subsidy policy to electric vehicles in China was initially launched in 2001. This study uses the perspective of the characteristics of subsidy policy and applies generalized propensity score matching (GPS) to estimate the impact of different subsidy policy intensities on the change in consumer demand for EVs and find the interval to optimize. The study shows that the optimization interval of the policy is in the 40%–70% treatment level, which maximizes the effect of the subsidy on China’s EVs. For a treatment effect lower than 40%, it is difficult to effectively create an incentive to enter the EVs market in China because consumers think that the product is difficult to satisfy the demand of too low technology; by contrast, for the treatment level higher than 70%, the cost of the high endurance mileage power battery increases exponentially, and the complementary effect of subsidies is insufficient. Consequently, we propose three suggestions: The government should 1) use big data technology to supervise subsidies and design a real-time reporting mechanism and punishment mechanism for subsidy-misuse; 2) adopt the incentive regulation to promote the battery range of new energy vehicles (e.g., optimizing the subsidy ladder, innovating the form of subsidies) and gradually eliminate low-technology product; and 3) reasonably design a targeted regulatory mechanism that increases the cost of fraud and breach of contract to encourage firms to truthfully report technical indicators.
Assignment Matrix Free Algorithms for On-line Estimation of Dynamic Origin-Destination Matrices
Authors: Castiglione Marisdea , Cantelmo Guido , Qurashi Moeid , Nigro Marialisa , Antoniou Constantinos
Published: March 2021

Dynamic Traffic Assignment (DTA) models represent fundamental tools to forecast traffic flows on road networks, assessing the effects of traffic management and transport policies. As biased models lead to incorrect predictions, which can cause inaccurate evaluations and huge social costs, the calibration of DTA models is an established and active research field. When it comes to estimating Origin-Destination (OD) demand flows, perhaps the most important input for DTA models, one algorithm suggested to outperform all the others for real-time applications: the Kalman Filter (KF). This paper introduces a non-linear Kalman Filter framework for online dynamic OD estimation that reduces the number of variables and can easily incorporate heterogeneous data sources to better explain the non-linear relationship between traffic data and time-dependent OD-flows. Specifically, we propose a model that takes advantage of Principal Component Analysis (PCA) to capture spatial correlations between variables and better exploit the local nature of a specific KF recently proposed in literature, the Local Ensemble Transformed Kalman filter (LETKF). The main advantage of the LETKF is that the Kalman gain is not explicitly formulated which means that, differently from other approaches proposed in the literature, there is no need to compute the assignment matrix or its approximation. The paper shows that the LETKF can easily incorporate different data sources, such as traffic counts and link speeds. Additionally, thanks to the PCA, the model can identify local patterns within the data and better explain the correlation between variables and data. The effectiveness of the proposed methodology is demonstrated first through synthetic experiments where non-linear functions are used to benchmark the model in different conditions and then on the real-world network of Vitoria, Spain (2,884 nodes, 5,799 links) using the mesoscopic simulator Aimsun. Results show that the proposed method leads to better state estimation performances with respect to other Ensemble-based Kalman filters, providing improvements as high as 64% in terms of traffic data reproduction with a 17-fold problem dimensionality reduction.
The Essential Involvement of the Omentum in the Peritoneal Defensive Mechanisms During Intra-Abdominal Sepsis
Authors: Liu Ying , Hu Jian-nan , Luo Ning , Zhao Jie , Liu Shu-chang , Ma Tao , Yao Yong-ming
Published: March 2021

Although the abilities of the omentum to alleviate inflammation and prevent infection have been revealed over the past decades, the underlying mechanisms remain largely unelucidated. Here, we demonstrated that the mortality of mice exposed to cecal ligation and puncture (CLP) and omentectomy was remarkably increased compared to those treated with CLP alone. Moreover, the efficacy of the omentum was associated with an impairment in intraperitoneal bacterial clearance together with an increase in the expression of proinflammatory cytokines. Besides, in response to peritoneal infections, the size and quantity of the omental milky spots (MSs) were increased tremendously and they also support innate-like B1 cell responses and local IgM production in the peritoneal cavity. Furthermore, not only the migration but also the functional activities of neutrophils were diminished in the absence of the omentum. These data collectively show that the omentum contributes more to peritoneal immune responses during septic peritonitis than has heretofore been recognized. Thus, harnessing the function of MS-containing omentum to increase its protective effectiveness may exert important biological and therapeutic implications for the control of intra-abdominal infections.
Tailored Modulation of Cellular Pro-inflammatory Responses With Disaccharide Lipid A Mimetics
Authors: Heine Holger , Adanitsch Florian , Peternelj Tina Tinkara , Haegman Mira , Kasper Christoph , Ittig Simon , Beyaert Rudi , Jerala Roman , Zamyatina Alla
Published: March 2021

Pro-inflammatory signaling mediated by Toll-like receptor 4 (TLR4)/myeloid differentiation-2 (MD-2) complex plays a crucial role in the instantaneous protection against infectious challenge and largely contributes to recovery from Gram-negative infection. Activation of TLR4 also boosts the adaptive immunity which is implemented in the development of vaccine adjuvants by application of minimally toxic TLR4 activating ligands. The modulation of pro-inflammatory responses via the TLR4 signaling pathway was found beneficial for management of acute and chronic inflammatory disorders including asthma, allergy, arthritis, Alzheimer disease pathology, sepsis, and cancer. The TLR4/MD-2 complex can recognize the terminal motif of Gram-negative bacterial lipopolysaccharide (LPS)—a glycophospholipid lipid A. Although immense progress in understanding the molecular basis of LPS-induced TLR4-mediated signaling has been achieved, gradual, and predictable TLR4 activation by structurally defined ligands has not yet been attained. We report on controllable modulation of cellular pro-inflammatory responses by application of novel synthetic glycolipids—disaccharide-based lipid A mimetics (DLAMs) having picomolar affinity for TLR4/MD-2. Using crystal structure inspired design we have developed endotoxin mimetics where the inherently flexible β(1 → 6)-linked diglucosamine backbone of lipid A is replaced by a conformationally restricted α,α-(1↔1)-linked disaccharide scaffold. The tertiary structure of the disaccharide skeleton of DLAMs mirrors the 3-dimensional shape of TLR4/MD-2 bound E. coli lipid A. Due to exceptional conformational rigidity of the sugar scaffold, the specific 3D organization of DLAM must be preserved upon interaction with proteins. These structural factors along with specific acylation and phosphorylation pattern can ensure picomolar affinity for TLR4 and permit efficient dimerization of TLR4/MD-2/DLAM complexes. Since the binding pose of lipid A in the binding pocket of MD-2 (±180°) is crucial for the expression of biological activity, the chemical structure of DLAMs was designed to permit a predefined binding orientation in the binding groove of MD-2, which ensured tailored and species-independent (human and mice) TLR4 activation. Manipulating phosphorylation and acylation pattern at the sugar moiety facing the secondary dimerization interface allowed for adjustable modulation of the TLR4-mediated signaling. Tailored modulation of cellular pro-inflammatory responses by distinct modifications of the molecular structure of DLAMs was attained in primary human and mouse immune cells, lung epithelial cells and TLR4 transfected HEK293 cells.
New Pathways for the Skin's Stress Response: The Cholinergic Neuropeptide SLURP-1 Can Activate Mast Cells and Alter Cytokine Production in Mice
Authors: Ertle Christoph M. , Rommel Frank R. , Tumala Susanne , Moriwaki Yasuhiro , Klein Jochen , Kruse Johannes , Gieler Uwe , Peters Eva M. J.
Published: March 2021

Background: The alpha7 nicotinic acetylcholine receptor (Chrna7) plays an essential anti-inflammatory role in immune homeostasis and was recently found on mast cells (MC). Psychosocial stress can trigger MC hyperactivation and increases pro-inflammatory cytokines in target tissues such as the skin. If the cholinergic system (CS) and Chrna7 ligands play a role in these cascades is largely unknown.

Objective: To elucidate the role of the CS in the response to psychosocial stress using a mouse-model for stress-triggered cutaneous inflammatory circuits.

Methods: Key CS markers (ACh, Ch, SLURP-1, SLURP-2, Lynx1, Chrm3, Chrna7, Chrna9, ChAT, VAChT, Oct3, AChE, and BChE) in skin and its MC (sMC), MC activation, immune parameters (TNFα, IL1β, IL10, TGFβ, HIF1α, and STAT3) and oxidative stress were analyzed in skin from 24 h noise-stressed mice and in cultured MC (cMC) from C57BL/6 or Chrna7-Knockout mice.

Results: First, Chrna7 and SLURP-1 mRNA were exclusively upregulated in stressed skin. Second, histomorphometry located Chrna7 and SLURP-1 in nerves and sMC and demonstrated upregulated contacts and increased Chrna7+ sMC in stressed skin, while 5 ng/mL SLURP-1 degranulated cMC. Third, IL1β+ sMC were high in stressed skin, and while SLURP-1 alone had no significant effect on cMC cytokines, it upregulated IL1β in cMC from Chrna7-KO and in IL1β-treated wildtype cMC. In addition, HIF1α+ sMC were high in stressed skin and Chrna7-agonist AR-R 17779 induced ROS in cMC while SLURP-1 upregulated TNFα and IL1β in cMC when HIF1α was blocked.

Conclusions: These data infer that the CS plays a role in the regulation of stress-sensitive inflammatory responses but may have a surprising pro-inflammatory effect in healthy skin, driving IL1β expression if SLURP-1 is involved.
Anti-Inflammatory (M2) Response Is Induced by a sp2-Iminosugar Glycolipid Sulfoxide in Diabetic Retinopathy
Authors: Cano-Cano Fátima , Alcalde-Estévez Elena , Gómez-Jaramillo Laura , Iturregui Marta , Sánchez-Fernández Elena M. , García Fernández José M. , Ortiz Mellet Carmen , Campos-Caro Antonio , López-Tinoco Cristina , Aguilar-Diosdado Manuel , Valverde Ángela M. , Arroba Ana I.
Published: March 2021

Diabetic retinopathy (DR) is one of the most common complications of Diabetes Mellitus (DM) and is directly associated with inflammatory processes. Currently, neuro-inflammation is considered an early event in DR and proceeds via microglia polarization. A hallmark of DR is the presence of retinal reactive gliosis. Here we report the beneficial effect of (SS,1R)-1-docecylsulfiny-5N,6O-oxomethylidenenojirimycin ((Ss)-DS-ONJ), a member of the sp2-iminosugar glycolipid (sp2-IGL) family, by decreasing iNOS and inflammasome activation in Bv.2 microglial cells exposed to pro-inflammatory stimuli. Moreover, pretreatment with (Ss)-DS-ONJ increased Heme-oxygenase (HO)-1 as well as interleukin 10 (IL10) expression in LPS-stimulated microglial cells, thereby promoting M2 (anti-inflammatory) response by the induction of Arginase-1. The results strongly suggest that this is the likely molecular mechanism involved in the anti-inflammatory effects of (SS)-DS-ONJ in microglia. (SS)-DS-ONJ further reduced gliosis in retinal explants from type 1 diabetic BB rats, which is consistent with the enhanced M2 response. In conclusion, targeting microglia polarization dynamics in M2 status by compounds with anti-inflammatory activities offers promising therapeutic interventions at early stages of DR.
Herpes Zoster in Solid Organ Transplantation: Incidence and Risk Factors
Authors: Kho Marcia M. L. , Roest Stefan , Bovée Dominique M. , Metselaar Herold J. , Hoek Rogier A. S. , van der Eijk Annemiek A. , Manintveld Olivier C. , Roodnat Joke I. , van Besouw Nicole M.
Published: March 2021

Background

Studies on herpes zoster (HZ) incidence in solid organ transplant (SOT) recipients report widely varying numbers. We investigated HZ incidence, severity, and risk factors in recipients of four different SOTs, with a follow-up time of 6–14 years.

Methods

Records of 1,033 transplant recipients after first heart (HTx: n = 211), lung (LuTx: n = 121), liver (LiTx: n = 258) and kidney (KTx: n = 443) transplantation between 2000 and 2014 were analyzed for VZV-PCR, clinical signs of HZ, and complications.

Results

HZ was diagnosed in 108 of 1,033 patients (10.5%): 36 HTx, 17 LuTx, 15 LiTx, and 40 KTx recipients. Overall HZ incidence rate after HTx (30.7 cases/1,000 person–years (PY)), LuTx (38.8 cases/1,000 PY), LiTx (22.7 cases/1,000 PY) and KTx (14.5 cases/1,000 PY) was significantly higher than in the general 50–70 year population. Multivariable analysis demonstrated age ≥50 years at transplantation (p = 0.038, RR 1.536), type of organ transplant (overall p = 0.002; LuTx p = 0.393; RR 1.314; LiTx p = 0.011, RR 0.444; KTx p = 0.034, RR 0.575), CMV prophylaxis (p = 0.043, RR 0.631) and type of anti-rejection therapy (overall p = 0.020; methylprednisolone p = 0.008, RR 0.475; r-ATG p = 0.64, RR1.194) as significant risk factors. Complications occurred in 33 of 108 (31%) patients (39% of HTx, 47% of LuTx, 20% of LiTx, 20% of KTx): post-herpetic neuralgia, disseminated disease, and cranial nerve involvement.

Conclusion

HZ incidence and severity in SOT recipients are most pronounced after heart and lung transplantation, in older patients, and when CMV prophylaxis is lacking.
CD8+ T Cells in GCA and GPA: Bystanders or Active Contributors?
Authors: Reitsema Rosanne D. , Boots Annemieke M. H. , van der Geest Kornelis S. M. , Sandovici Maria , Heeringa Peter , Brouwer Elisabeth
Published: March 2021

Vasculitis refers to inflammation of blood vessels and can cause a variety of serious complications depending on which vessels are affected. Two different forms of vasculitis are Giant Cell Arteritis (GCA) and Granulomatosis with Polyangiitis (GPA). GCA is the most common form of vasculitis in adults affecting the large arteries and can lead to visual impairment and development of aneurysms. GPA affects small- and medium-sized blood vessels predominantly in the lungs and kidneys resulting in organ failure. Both diseases can potentially be fatal. Although the pathogenesis of GCA and GPA are incompletely understood, a prominent role for CD4+ T cells has been implicated in both diseases. More recently, the role of CD8+ T cells has gained renewed interest. CD8+ T cells are important players in the adaptive immune response against intracellular microorganisms. After a general introduction on the different forms of vasculitis and their association with infections and CD8+ T cells, we review the current knowledge on CD8+ T-cell involvement in the immunopathogenesis of GCA and GPA focusing on phenotypic and functional features of circulating and lesional CD8+ T cells. Furthermore, we discuss to which extent aging is associated with CD8+ T-cell phenotype and function in GCA and GPA.
Current and Future Therapeutic Approaches for Thymic Stromal Cell Defects
Authors: Kreins Alexandra Y. , Bonfanti Paola , Davies E. Graham
Published: March 2021

Inborn errors of thymic stromal cell development and function lead to impaired T-cell development resulting in a susceptibility to opportunistic infections and autoimmunity. In their most severe form, congenital athymia, these disorders are life-threatening if left untreated. Athymia is rare and is typically associated with complete DiGeorge syndrome, which has multiple genetic and environmental etiologies. It is also found in rare cases of T-cell lymphopenia due to Nude SCID and Otofaciocervical Syndrome type 2, or in the context of genetically undefined defects. This group of disorders cannot be corrected by hematopoietic stem cell transplantation, but upon timely recognition as thymic defects, can successfully be treated by thymus transplantation using cultured postnatal thymic tissue with the generation of naïve T-cells showing a diverse repertoire. Mortality after this treatment usually occurs before immune reconstitution and is mainly associated with infections most often acquired pre-transplantation. In this review, we will discuss the current approaches to the diagnosis and management of thymic stromal cell defects, in particular those resulting in athymia. We will discuss the impact of the expanding implementation of newborn screening for T-cell lymphopenia, in combination with next generation sequencing, as well as the role of novel diagnostic tools distinguishing between hematopoietic and thymic stromal cell defects in facilitating the early consideration for thymus transplantation of an increasing number of patients and disorders. Immune reconstitution after the current treatment is usually incomplete with relatively common inflammatory and autoimmune complications, emphasizing the importance for improving strategies for thymus replacement therapy by optimizing the current use of postnatal thymus tissue and developing new approaches using engineered thymus tissue.