bluuebunny/crossref_metadata_2025 huggingface dataset:
Mathematical Modeling and Simulation Provides Evidence for New Strategies of Ovarian Stimulation
Authors: Fischer Sophie , Ehrig Rainald , Schäfer Stefan , Tronci Enrico , Mancini Toni , Egli Marcel , Ille Fabian , Krüger Tillmann H. C. , Leeners Brigitte , Röblitz Susanna
Published: March 2021

New approaches to ovarian stimulation protocols, such as luteal start, random start or double stimulation, allow for flexibility in ovarian stimulation at different phases of the menstrual cycle. It has been proposed that the success of these methods is based on the continuous growth of multiple cohorts (“waves”) of follicles throughout the menstrual cycle which leads to the availability of ovarian follicles for ovarian controlled stimulation at several time points. Though several preliminary studies have been published, their scientific evidence has not been considered as being strong enough to integrate these results into routine clinical practice. This work aims at adding further scientific evidence about the efficiency of variable-start protocols and underpinning the theory of follicular waves by using mathematical modeling and numerical simulations. For this purpose, we have modified and coupled two previously published models, one describing the time course of hormones and one describing competitive follicular growth in a normal menstrual cycle. The coupled model is used to test ovarian stimulation protocolsin silico. Simulation results show the occurrence of follicles in a wave-like manner during a normal menstrual cycle and qualitatively predict the outcome of ovarian stimulation initiated at different time points of the menstrual cycle.
Aldose Reductase: An Emerging Target for Development of Interventions for Diabetic Cardiovascular Complications
Authors: Jannapureddy Sravya , Sharma Mira , Yepuri Gautham , Schmidt Ann Marie , Ramasamy Ravichandran
Published: March 2021

Diabetes is a leading cause of cardiovascular morbidity and mortality. Despite numerous treatments for cardiovascular disease (CVD), for patients with diabetes, these therapies provide less benefit for protection from CVD. These considerations spur the concept that diabetes-specific, disease-modifying therapies are essential to identify especially as the diabetes epidemic continues to expand. In this context, high levels of blood glucose stimulate the flux via aldose reductase (AR) pathway leading to metabolic and signaling changes in cells of the cardiovascular system. In animal models flux via AR in hearts is increased by diabetes and ischemia and its inhibition protects diabetic and non-diabetic hearts from ischemia-reperfusion injury. In mouse models of diabetic atherosclerosis, human AR expression accelerates progression and impairs regression of atherosclerotic plaques. Genetic studies have revealed that single nucleotide polymorphisms (SNPs) of the ALD2 (human AR gene) is associated with diabetic complications, including cardiorenal complications. This Review presents current knowledge regarding the roles for AR in the causes and consequences of diabetic cardiovascular disease and the status of AR inhibitors in clinical trials. Studies from both human subjects and animal models are presented to highlight the breadth of evidence linking AR to the cardiovascular consequences of diabetes.
Microgrid Policies: A Review of Technologies and Key Drivers of Thailand
Authors: Meenual Thongchai , Usapein Parnuwat
Published: March 2021

Microgrids have been emerging and playing valuable roles in several parts of society, from academia of scholars to the energy supply industry of professional practitioners. A microgrid policy appeared in the Thailand 2015 energy development plan. There are many microgrids in Thailand. The first smart microgrid in Thailand is in active operation. Some microgrids are no longer functioning. Other microgrids continue to serve their customers. The remaining microgrid projects are in the process of development. Most present microgrids in Thailand are driven by public policy and legal flexibility. The objective of this research is to investigate the compatible microgrid technology in Thailand and explore the key drivers of microgrid policies in Thailand. The research methodology applied in this research includes data collection (i.e., a document study, interview, group discussion, and microgrid project participation and observation), as well as data analysis and conclusion. The findings of the research show that: in Thailand, the desired microgrid technologies are compatible with 1) inputs of potential local renewable energy resources of solar, wind, biomass, and mini-hydro, and 2) small gaps of human resource capabilities to deal with the technology utilization. The key drivers of the Thailand microgrid policy are 1) electricity access, 2) wealth creation and distribution, 3) environmental protection, and 4) technology development.
Environmental Benefit and Investment Value of Hydrogen-Based Wind-Energy Storage System
Authors: Xue Qing , Wang Zhen , Zhang Yuqing
Published: March 2021

Alongside the rapid expansion of wind power installation in China, wind curtailment is also mounting rapidly due to China’s energy endowment imbalance. The hydrogen-based wind-energy storage system becomes an alternative to solve the puzzle of wind power surplus. This article introduced China’s energy storage industry development and summarized the advantages of hydrogen-based wind-energy storage systems. From the perspective of resource conservation, it estimated the environmental benefits of hydrogen-based wind-energy storages. This research also builds a valuation model based on the Real Options Theory to capture the distinctive flexible charging and discharging features of the hydrogen-based wind-energy storage systems. Based on the model, simulation results, including the investment value and operation decision of the hydrogen energy storage system with different electricity prices, system parameters, and different levels of subsidies, are presented. The results show that the hydrogen storage system fed with the surplus wind power can annually save approximately 2.19–3.29 million tons of standard coal consumption. It will reduce 3.31–4.97 million tons of CO2, SO2, NOx, and PM, saving as much as 286.6–429.8 million yuan of environmental cost annually on average. The hydrogen-based wind-energy storage system’s value depends on the construction investment and operating costs and is also affected by the mean-reverting nature and jumps or spikes in electricity prices. The market-oriented reform of China’s power sector is conducive to improve hydrogen-based wind-energy storage systems’ profitability. At present, subsidies are still essential to reduce initial investment and attract enterprises to participate in hydrogen energy storage projects.
Declines in an Augur Buzzard Buteo augur Population in a Region of Increasing Human Development
Authors: Eichenwald Adam J. , Amar Arjun , Tyrrell Peter , Buechley Evan R. , Virani Munir Z.
Published: March 2021

As with many areas in Africa, Kenya has witnessed rapid human development in recent decades, including an increase in urbanization and an intensification of agriculture. The impact of these land use changes on wildlife populations have, however, rarely been examined. The Augur Buzzard is a widespread raptor species, thought to adapt relatively well to human alterations of habitat. In this study, we explore trends in Augur Buzzard (Buteo augur) territory occupancy over nearly two decades around Lake Naivasha, Kenya, in relation to land-use changes, particularly expansion in human housing and flower farms. We hypothesized that these changes would cause population declines in this species within our study area. Using remote-sensed satellite imagery, we found that human development (agriculture and human settlement) increased from 9 to 24% of the study area from 1995 to 2014. We found a 47% decline in active territories over this same time period, representing an annualized decline of 3.1%. Based on the length of three generations this would qualify this species to be uplisted to at least Vulnerable in our study area, raising our concerns that the same pattern may be occurring across the species’ range. We then explored whether abandonment of individual territories was associated with either (i) the current amount or (ii) the change in human development within a range of buffer circles of varying radii (0.1–5.0 km). Contrary to our expectations, no associations were found between human development and territorial abandonment, and thus we could not attribute specific territorial abandonment to these broad scale anthropogenic land cover changes. We encourage further research to investigate whether territorial abandonment may be associated with either finer resolution (habitat specific) changes, or sources of direct mortality, for example human persecution or electrocutions. These factors might explain the decline in this population better than broader scale increases in anthropogenic land cover.
Gene Expression Analysis Suggests Immunological Changes of Peripheral Blood Monocytes in the Progression of Patients With Coronary Artery Disease
Authors: Wang Chunyue , Song Chenxi , Liu Qianqian , Zhang Rui , Fu Rui , Wang Hao , Yin Dong , Song Weihua , Zhang Haitao , Dou Kefei
Published: March 2021

Objectives

To analyze the gene expression profile of peripheral blood monocytes in different stages of coronary artery disease (CAD) by transcriptome sequencing, and to explore potential genes and pathway involved in CAD pathogenesis.

Methods

According to the screening of coronary angiography and quality control of blood samples, eight intermediate coronary lesion patients were selected, then eight patients with acute myocardial infarction, and eight patients with normal coronary angiography were matched by age and gender. Transcriptomics sequencing was conducted for the peripheral blood monocytes of these 24 samples by using the Illumina HiSeq high-throughput platform. Then, differentially expressed genes (DEGs) were analyzed. Gene Ontology (GO) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation, and protein-protein interaction (PPI) network were applied to annotate the potential functions of DEGs.

Results

Compared with the normal coronary angiography group, we identified a total of 169 DEGs in the intermediate coronary lesion group, which were significantly enriched in 59 GO terms and 17 KEGG pathways. Compared with the normal coronary angiography group, we found a total of 2,028 DEGs, which were significantly enriched in 311 GO terms and 20 KEGG pathways in the acute myocardial infarction group. The cross-comparison between normal versus intermediate coronary lesion group, and normal versus acute myocardial infarction group included 98 differential genes with 65 up regulated and 33 down regulated genes, which were significantly enriched in 46 GO terms and 10 KEGG pathways. During the progression of CAD, there was a significant up-regulated expression of CSF3, IL-1A, CCR7, and IL-18, and down-regulated expression of MAPK14. Besides GO items such as inflammatory response was significantly enriched, KEGG analysis showed the most remarkable enrichments in IL-17 signaling pathway and cytokine-cytokine receptor interactions.

Conclusions

Transcriptomics profiles vary in patients with different severity of CAD. CSF3, IL-1A, CCR7, IL-18, and MAPK14, as well as IL-17 signaling pathway and cytokine and cytokine receptor interaction signaling pathway related with inflammatory response might be the potential biomarker and targets for the treatment of coronary artery disease.
Introduction of Non-natural Amino Acids Into T-Cell Epitopes to Mitigate Peptide-Specific T-Cell Responses
Authors: Azam Aurélien , Mallart Sergio , Illiano Stephane , Duclos Olivier , Prades Catherine , Maillère Bernard
Published: March 2021

Non-natural modifications are widely introduced into peptides to improve their therapeutic efficacy, but their impact on immunogenicity remains largely unknown. As the CD4 T-cell response is a key factor in triggering immunogenicity, we investigated the effect of introducing D-amino acids (Daa), amino isobutyric acid (Aib), N-methylation, Cα-methylation, reduced amide, and peptoid bonds into an immunoprevalent T-cell epitope on binding to a set of HLA-DR molecules, recognition, and priming of human T cells. Modifications are differentially accepted at multiple positions, but are all tolerated in the flanking regions. Introduction of Aib and Daa in the binding core had the most deleterious effect on binding to HLA-DR molecules and T-cell activation. Their introduction at the positions close to the P1 anchor residue abolished T-cell priming, suggesting they might be sufficient to dampen peptide immunogenicity. Other modifications led to variable effects on binding to HLA-DR molecules and T-cell reactivity, but none exhibited an increased ability to stimulate T cells. Altogether, non-natural modifications appear generally to diminish binding to HLA-DR molecules and hence T-cell stimulation. These data might guide the design of therapeutic peptides to make them less immunogenic.
From ELISA to Immunosorbent Tandem Mass Spectrometry Proteoform Analysis: The Example of CXCL8/Interleukin-8
Authors: Metzemaekers Mieke , Abouelasrar Salama Sara , Vandooren Jennifer , Mortier Anneleen , Janssens Rik , Vandendriessche Sofie , Ganseman Eva , Martens Erik , Gouwy Mieke , Neerinckx Barbara , Verschueren Patrick , De Somer Lien , Wouters Carine , Struyf Sofie , Opdenakker Ghislain , Van Damme Jo , Proost Paul
Published: March 2021

With ELISAs one detects the ensemble of immunoreactive molecules in biological samples. For biomolecules undergoing proteolysis for activation, potentiation or inhibition, other techniques are necessary to study biology. Here we develop methodology that combines immunosorbent sample preparation and nano-scale liquid chromatography—tandem mass spectrometry (nano-LC-MS/MS) for proteoform analysis (ISTAMPA) and apply this to the aglycosyl chemokine CXCL8. CXCL8, the most powerful human chemokine with neutrophil chemotactic and –activating properties, occurs in different NH2-terminal proteoforms due to its susceptibility to site-specific proteolytic modification. Specific proteoforms display up to 30-fold enhanced activity. The immunosorbent ion trap top-down mass spectrometry-based approach for proteoform analysis allows for simultaneous detection and quantification of full-length CXCL8(1-77), elongated CXCL8(-2-77) and all naturally occurring truncated CXCL8 forms in biological samples. For the first time we demonstrate site-specific proteolytic activation of CXCL8 in synovial fluids from patients with chronic joint inflammation and address the importance of sample collection and processing.
Sex Proportionality in Pre-clinical and Clinical Trials: An Evaluation of 22 Marketing Authorization Application Dossiers Submitted to the European Medicines Agency
Authors: Dekker Marieke J. H. J. , de Vries Sieta T. , Versantvoort Carolien H. M. , Drost-van Velze Ellen G. E. , Bhatt Mansi , van Meer Peter J. K. , Havinga Ineke K. , Gispen-de Wied Christine C. , Mol Peter G. M.
Published: March 2021

This study assessed to what extent women were included in all phases of drug development; whether the clinical studies in the marketing authorization application dossiers include information per sex; and explored whether there are differences between women and men in the drugs' efficacy and safety. Data were extracted from dossiers submitted to the European Medicines Agency. Twenty-two dossiers of drugs approved between 2011 and 2015 for the treatment of various diseases were included. Female animals were included in only 9% of the pharmacodynamics studies, but female and male animals were included in all toxicology studies. Although fewer women than men were included in the clinical studies used to evaluate pharmacokinetics (PK) (29 to 40% women), all dossiers contained sex-specific PK parameter estimations. In the phase III trials, inclusion of women was proportional to disease prevalence for depression, epilepsy, thrombosis, and diabetes [participation to prevalence ratio (PPR) range: 0.91–1.04], but women were considered underrepresented for schizophrenia, hepatitis C, hypercholesterolemia, HIV, and heart failure (PPR range: 0.49-0.74). All dossiers contained sex-specific subgroup analyses of efficacy and safety. There seemed to be higher efficacy for women in one dossier and a trend toward lower efficacy in another dossier. More women had adverse events in both treatment (73.0 vs. 70.6%, p < 0.001) and placebo groups (69.5 vs. 65.5%, p < 0.001). In conclusion, women were included throughout all phases of clinical drug research, and sex-specific information was available in the evaluated dossiers. The included number of women was, however, not always proportional to disease prevalence rates.
Overexpression of Efflux Pumps, Mutations in the Pumps’ Regulators, Chromosomal Mutations, and AAC(6′)-Ib-cr Are Associated With Fluoroquinolone Resistance in Diverse Sequence Types of Neonatal Septicaemic Acinetobacter baumannii: A 7-Year Single Center Study
Authors: Roy Subhasree , Chatterjee Somdatta , Bhattacharjee Amrita , Chattopadhyay Pinaki , Saha Bijan , Dutta Shanta , Basu Sulagna
Published: March 2021

This study investigates susceptibility toward three fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin), multiple fluoroquinolone-resistance mechanisms, and epidemiological relationship of neonatal septicaemic Acinetobacter baumannii. Previous studies on fluoroquinolone resistance in A. baumannii focused primarily on ciprofloxacin susceptibility and assessed a particular mechanism of resistance; a more holistic approach was taken here. Epidemiological relationship was evaluated by Multi Locus Sequence Typing. Minimum Inhibitory Concentrations of fluoroquinolones was determined with and without efflux pump inhibitors. Overexpression of efflux pumps, resistance-nodulation-cell-division (RND)-type, and multidrug and toxic compound extrusion (MATE)-type efflux pumps were evaluated by reverse transcriptase-qPCR. Mutations within regulatory proteins (AdeRS, AdeN, and AdeL) of RND-pumps were examined. Chromosomal mutations, presence of qnr and aac(6′)-Ib-cr were investigated. A. baumannii were highly diverse as 24 sequence-types with seven novel STs (ST-1440/ST-1441/ST-1481/ST-1482/ST-1483/ST-1484/ST-1486) were identified among 47 A. baumannii. High resistance to ciprofloxacin (96%), levofloxacin (92%), and particularly moxifloxacin (90%) was observed, with multiple mechanisms being active. Resistance to 4th generation fluoroquinolone (moxifloxacin) in neonatal isolates is worrisome. Mutations within GyrA (S83L) and ParC (S80L) were detected in more than 90% of fluoroquinolone-resistant A. baumannii (FQRAB) spread across 10 different clonal complexes (CC1/CC2/CC10/CC25/CC32/CC126/CC149/CC216/CC218/CC513). Efflux-based FQ resistance was found in 65% of FQRAB with ≥2 different active pumps in 38% of strains. Overexpression of adeB was highest (2.2−34-folds) followed by adeJ, adeG, and abeM. Amino acid changes in the regulators (AdeRS/AdeN/AdeL) either as single or multiple substitutions substantiated the overexpression of the pumps. Diverse mutations within AdeRS were detected among different CCs whereas mutations within AdeN linked to CC10 and CC32. Chromosomal mutations and active efflux pumps were detected simultaneously among 64% of FQRAB. Presence of aac(6′)-Ib-cr was also high (74% of FQRAB) but qnrS were absent. As most FQRABs had chromosomal mutations, this was considered predominant, however, isolates where pumps were also active had higher MIC values, establishing the critical role of the efflux pumps. The high variability of FQ susceptibility among FQRAB, possessing the same set of mutations in gyrA, parC, and efflux pump regulators, was also noted. This reveals the complexity of interpreting the interplay of multiple resistance mechanisms in A. baumannii.
The Relationship Between Microbiomes and Selective Regimes in the Sponge Genus Ircinia
Authors: Kelly Joseph B. , Carlson David E. , Low Jun Siong , Rice Tyler , Thacker Robert W.
Published: March 2021

Sponges are often densely populated by microbes that benefit their hosts through nutrition and bioactive secondary metabolites; however, sponges must simultaneously contend with the toxicity of microbes and thwart microbial overgrowth. Despite these fundamental tenets of sponge biology, the patterns of selection in the host sponges’ genomes that underlie tolerance and control of their microbiomes are still poorly understood. To elucidate these patterns of selection, we performed a population genetic analysis on multiple species ofIrciniafrom Belize, Florida, and Panama using anFST-outlier approach on transcriptome-annotated RADseq loci. As part of the analysis, we delimited species boundaries among seven growth forms ofIrcinia. Our analyses identified balancing selection in immunity genes that have implications for the hosts’ tolerance of high densities of microbes. Additionally, our results support the hypothesis that each of the seven growth forms constitutes a distinctIrciniaspecies that is characterized by a unique microbiome. These results illuminate the evolutionary pathways that promote stable associations between host sponges and their microbiomes, and that potentially facilitate ecological divergence amongIrciniaspecies.
Environmental Plasticity of the RNA Content of Staphylococcus aureus Extracellular Vesicles
Authors: Luz Brenda Silva Rosa Da , Nicolas Aurélie , Chabelskaya Svetlana , Rodovalho Vinícius de Rezende , Le Loir Yves , Azevedo Vasco Ariston de Carvalho , Felden Brice , Guédon Eric
Published: March 2021

The roles of bacterial extracellular vesicles (EVs) in cell-to-cell signaling are progressively being unraveled. These membranous spheres released by many living cells carry various macromolecules, some of which influence host-pathogen interactions. Bacterial EVs contain RNA, which may serve in communicating with their infected hosts. Staphylococcus aureus, an opportunistic human and animal pathogen, produces EVs whose RNA content is still poorly characterized. Here, we investigated in depth the RNA content of S. aureus EVs. A high-throughput RNA sequencing approach identified RNAs in EVs produced by the clinical S. aureus strain HG003 under different environmental conditions: early- and late-stationary growth phases, and presence or absence of a sublethal vancomycin concentration. On average, sequences corresponding to 78.0% of the annotated transcripts in HG003 genome were identified in HG003 EVs. However, only ~5% of them were highly covered by reads (≥90% coverage) indicating that a large fraction of EV RNAs, notably mRNAs and sRNAs, were fragmented in EVs. According to growth conditions, from 86 to 273 highly covered RNAs were identified into the EVs. They corresponded to 286 unique RNAs, including 220 mRNAs. They coded for numerous virulence-associated factors (hld encoded by the multifunctional sRNA RNAIII, agrBCD, psmβ1, sbi, spa, and isaB), ribosomal proteins, transcriptional regulators, and metabolic enzymes. Twenty-eight sRNAs were also detected, including bona fide RsaC. The presence of 22 RNAs within HG003 EVs was confirmed by reverse transcription quantitative PCR (RT-qPCR) experiments. Several of these 286 RNAs were shown to belong to the same transcriptional units in S. aureus. Both nature and abundance of the EV RNAs were dramatically affected depending on the growth phase and the presence of vancomycin, whereas much less variations were found in the pool of cellular RNAs of the parent cells. Moreover, the RNA abundance pattern differed between EVs and EV-producing cells according to the growth conditions. Altogether, our findings show that the environment shapes the RNA cargo of the S. aureus EVs. Although the composition of EVs is impacted by the physiological state of the producing cells, our findings suggest a selective packaging of RNAs into EVs, as proposed for EV protein cargo. Our study shedds light to the possible roles of potentially functional RNAs in S. aureus EVs, notably in host-pathogen interactions.
Influence of Disease-Causing Mutations on Protein Structural Networks
Authors: Prabantu Vasam Manjveekar , Naveenkumar Nagarajan , Srinivasan Narayanaswamy
Published: March 2021

The interactions between residues in a protein tertiary structure can be studied effectively using the approach of protein structure network (PSN). A PSN is a node-edge representation of the structure with nodes representing residues and interactions between residues represented by edges. In this study, we have employed weighted PSNs to understand the influence of disease-causing mutations on proteins of known 3D structures. We have used manually curated information on disease mutations from UniProtKB/Swiss-Prot and their corresponding protein structures of wildtype and disease variant from the protein data bank. The PSNs of the wildtype and disease-causing mutant are compared to analyse variation of global and local dissimilarity in the overall network and at specific sites. We study how a mutation at a given site can affect the structural network at a distant site which may be involved in the function of the protein. We have discussed specific examples of the disease cases where the protein structure undergoes limited structural divergence in their backbone but have large dissimilarity in their all atom networks and vice versa, wherein large conformational alterations are observed while retaining overall network. We analyse the effect of variation of network parameters that characterize alteration of function or stability.
The Effects of Autophagy-Related Genes and lncRNAs in Therapy and Prognosis of Colorectal Cancer
Authors: Yang Yang , Feng Mingyang , Bai LiangLiang , Zhang Mengxi , Zhou Kexun , Liao Weiting , Lei Wanting , Zhang Nan , Huang Jiaxing , Li Qiu
Published: March 2021

Cellular autophagy plays an important role in the occurrence and development of colorectal cancer (CRC). Whether autophagy-related genes and lncRNAs can be used as ideal markers in CRC is still controversial. The purpose of this study is to identify novel treatment and prognosis markers of CRC. We downloaded transcription and clinical data of CRC from the GEO (GSE40967, GSE12954, GSE17536) and TCGA database, screened for differentially autophagy-related genes (DEAGs) and lncRNAs, constructed prognostic model, and analyzed its relationship with immune infiltration. TCGA and GEO datasets (GSE12954 and GSE17536) were used to validate the effect of the model. Oncomine database and Human Protein Atlas verified the expression of DEAGs. We obtained a total of 151 DEAGs in three verification sets collaboratively. Then we constructed a risk prognostic model through Lasso regression to obtain 15 prognostic DEAGs from the training set and verified the risk prognostic model in three verification sets. The low-risk group survived longer than the high-risk group. Age, gender, pathological stage, and TNM stage were related to the prognostic risk of CRC. On the other hand, BRAF status, RFS event, and tumor location are considered as most significant risk factors of CRC in the training set. Furthermore, we found that the immune score of the low-risk group was higher. The content of CD8 + T cells, active NK cells, macrophages M0, macrophages M1, and active dendritic cells was noted more in the high-risk group. The content of plasma cells, resting memory CD4 + T cells, resting NK cells, resting mast cells, and neutrophil cells was higher in the low-risk group. After all, the Oncomine database and immunohistochemistry verified that the expression level of most key autophagy-related genes was consistent with the results that we found. In addition, we obtained six lncRNAs co-expressed with DEAGs from the training set and found that the survival time was longer in the low-risk group. This finding was verified in the verification set and showed same trend to the results mentioned above. In the final analysis, these results indicate that autophagy-related genes and lncRNAs can be used as prognostic and therapeutic markers for CRC.
Circular RNA CHST15 Sponges miR-155-5p and miR-194-5p to Promote the Immune Escape of Lung Cancer Cells Mediated by PD-L1
Authors: Yang Jianru , Jia Yang , Wang Bing , Yang Shengrong , Du Kun , Luo Yujie , Li Yunhe , Zhu Bing
Published: March 2021

Background

The effects of up-regulated CircCHST15 on lung cancer remained unclear. In this study, the role of CircCHST15 in lung cancer was investigated.

Methods

Dual-luciferase reporter verified the bioinformatics prediction that CircCHST15 targeted miR-155-5p and miR-194-5p. The correlation between CircCHST15 and PD-L1 was analyzed by Pearson analysis. CCK-8 and colony formation was performed to determine the viability and proliferation of lung cancer cells. After the lung cancer (subcutaneous-xenotransplant) model was established in mice, the T cell subtype and related cytokines in mouse tumor tissues were detected by flow cytometry and ELISA. Moreover, the expressions of CircCHST15, miR-155-5p, miR-194-5p, immune-related, and proliferation-related factors of the lung cancer cells or mice tumor tissues were detected by immunohistochemistry, RT-qPCR, or Western blot.

Results

CircCHST15 and PD-L1 were high-expressed in lung cancer, and the two was positively correlated. CircCHST15 targeted miR-155-5p and miR-194-5p, the later further targeted PD-L1. Lung cancer cell viability and proliferation were increased by miR-155-5p and inhibited by miR-194-5p. CircCHST15 located in the cytoplasm promoted tumor growth, down-regulated the expressions of miR-155-5p and miR-194-5p, and up-regulated the expressions of PD-L1, Ki-67, PCNA, CCL17, CCL22, IFN-γ, TNF-β, and IL-10. Also, CircCHST15 decreased the CD8+ cells in mouse blood and tumor, but increased the Tregs in mouse tumor. PD-L1 inhibitor showed an opposite effect to CircCHST15 on mouse tumors.

Conclusion

CircCHST15 sponged miR-155-5p and miR-194-5p to promote the PD-L1-mediated immune escape of lung cancer cells.
Treatment Patterns and Survival of Patients With Advanced Non-Small Cell Lung Cancer Guided by Comprehensive Genomic Profiling: Real-World Single-Institute Study in China
Authors: Lv Weize , Cheng Hua , Shao Di , Wei Yajun , Zhu Weiping , Wu Kui , Jiang Wenxi , Hu Liyang , Sha Zhou , Zhong Beilong , Pei Xiaofeng
Published: March 2021

Although the National Comprehensive Cancer Network and the Chinese Society of Clinical Oncology guidelines recommend comprehensive genomic profiling of lung adenocarcinoma, it has not been widely applied in Chinese hospitals. This observational study aimed to determine real-world evidence of whether comprehensive genomic profiling can benefit the survival of patients with lung cancer. We investigated the frequency of genomic alterations, treatment strategies, and clinical outcomes in 233 patients with advanced non-small cell lung carcinoma who were routinely screened using a 508-gene panel. The most prevalent drivers were mutations of EGFR (51%), KRAS (9%), PIK3CA (7%), ALK (7%), MET (6%), and BRAF (5%). Mutations in tumor suppressor genes included TP53, KEAP1, RB1, PTEN, and APC. Median overall survival (OS) was significantly shorter among patients harboring KRAS (mutant, n = 17; WT, n = 154) and TP53 (mutant, n = 103; WT n =68) mutations (11.3 vs. 24.0 months; P = 0.16 and 18.7 vs. 28.7 months; P = 0.018, respectively). The OS was longer among patients with tumors harboring EGFR (P = 0.069) and ALK (P = 0.51) mutations. Most patients (65.4%) with the driver gene-positive (EGFR, ALK, and ROS1) tumors were received TKI treatment, whereas those with driver gene wild tumors (53.1%) chose platinum-based therapy. Univariate and multivariate analyses associated a shorter OS among patients with tumors harboring concomitant TP53 and EGFR mutations. These findings provide additional evidence from real-world on the potential importance of targeted therapies as a treatment option in NSCLC patients harboring clinically actionable mutation.
Reactive Oxygen Species Rewires Metabolic Activity in Acute Myeloid Leukemia
Authors: Robinson Andrew J. , Davies Sara , Darley Richard L. , Tonks Alex
Published: March 2021

Acute myeloid leukemia (AML) is a heterogeneous disease with poor clinical outcomes. We have previously shown that constitutive activation of NADPH oxidase 2 (NOX2), resulting in over-production of reactive oxygen species (ROS), occurs in over 60% of AML patients. We have also shown that increased ROS production promotes increased glucose uptake and proliferation in AML cells, mediated by changes in carbohydrate metabolism. Given that carbohydrate, lipid, and protein metabolisms are all intricately interconnected, we aimed to examine the effect of cellular ROS levels on these pathways and establish further evidence that ROS rewires metabolism in AML. We carried out metabolomic profiling of AML cell lines in which NOX2-derived ROS production was inhibited and conversely in cells treated with exogenous H2O2. We report significant ROS-specific metabolic alterations in sphingolipid metabolism, fatty acid oxidation, purine metabolism, amino acid homeostasis and glycolysis. These data provide further evidence of ROS directed metabolic changes in AML and the potential for metabolic targeting as novel therapeutic arm to combat this disease.
High Dynamic Range Structured Illumination Microscope Based on Multiple Exposures
Authors: Liang Yong , Chen Xiaohu , Sun Zhenglong , Wen Gang , Chen Chong , Wang Libo , Jin Xin , Zhang Jie , Yang Guang , Gao Jing , Li Hui , Li Simin
Published: March 2021

Structured illumination microscope (SIM) can double the spatial resolution by using fringed pattern illumination. However, for samples with large intra-scene dynamic ranges, such as clustered objects, SIM fails to reconstruct high-quality images and often exhibits strong artifacts. Herein, we present a high dynamic range SIM (HDR-SIM) method using a multi-exposure acquisition strategy. With HDR-SIM, individual and clustered microspheres and vesicles with 420 times intensity differences can be visualized in the same scene while the delicate structures of the sample were preserved effectively.
Regulatory Function of Sympathetic Innervation on the Endo/Lysosomal Trafficking of Acetylcholine Receptor
Authors: Straka Tatjana , Schröder Charlotte , Roos Andreas , Kollipara Laxmikanth , Sickmann Albert , Williams Marion Patrick Ivey , Hafner Mathias , Khan Muzamil Majid , Rudolf Rüdiger
Published: March 2021

Recent studies have demonstrated that neuromuscular junctions are co-innervated by sympathetic neurons. This co-innervation has been shown to be crucial for neuromuscular junction morphology and functional maintenance. To improve our understanding of how sympathetic innervation affects nerve–muscle synapse homeostasis, we here used in vivo imaging, proteomic, biochemical, and microscopic approaches to compare normal and sympathectomized mouse hindlimb muscles. Live confocal microscopy revealed reduced fiber diameters, enhanced acetylcholine receptor turnover, and increased amounts of endo/lysosomal acetylcholine-receptor-bearing vesicles. Proteomics analysis of sympathectomized skeletal muscles showed that besides massive changes in mitochondrial, sarcomeric, and ribosomal proteins, the relative abundance of vesicular trafficking markers was affected by sympathectomy. Immunofluorescence and Western blot approaches corroborated these findings and, in addition, suggested local upregulation and enrichment of endo/lysosomal progression and autophagy markers, Rab 7 and p62, at the sarcomeric regions of muscle fibers and neuromuscular junctions. In summary, these data give novel insights into the relevance of sympathetic innervation for the homeostasis of muscle and neuromuscular junctions. They are consistent with an upregulation of endocytic and autophagic trafficking at the whole muscle level and at the neuromuscular junction.
Effect of Chronic Exercise Training on Blood Lactate Metabolism Among Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis
Authors: Zhao Tong , Le Shenglong , Freitag Nils , Schumann Moritz , Wang Xiuqiang , Cheng Sulin
Published: March 2021

Purpose: To assess the effect of chronic exercise training on blood lactate metabolism at rest (i.e., basal lactate concentrations) and during exercise (i.e., blood lactate concentration at a fixed load, load at a fixed blood lactate concentration, and load at the individual blood lactate threshold) among patients with type 2 diabetes mellitus (T2DM).

Methods: PubMed (MedLine), Embase, Web of Science, and Scopus were searched. Randomized controlled trials, non-randomized controlled trials, and case-control studies using chronic exercise training (i.e., 4 weeks) and that assessed blood lactate concentrations at rest and during exercise in T2DM patients were included.

Results: Thirteen studies were eligible for the systematic review, while 12 studies with 312 participants were included into the meta-analysis. In the pre-to-post intervention meta-analysis, chronic exercise training had no significant effect on changes in basal blood lactate concentrations (standardized mean difference (SMD) = −0.20; 95% CI, −0.55 to 0.16; p = 0.28), and the results were similar when comparing the effect of intervention and control groups. Furthermore, blood lactate concentration at a fixed load significantly decreased (SMD = −0.73; 95% CI, −1.17 to −0.29; p = 0.001), while load at a fixed blood lactate concentration increased (SMD = 0.40; 95% CI, 0.07 to 0.72; p = 0.02) after chronic exercise training. No change was observed in load at the individual blood lactate threshold (SMD = 0.28; 95% CI, −0.14 to 0.71; p = 0.20).

Conclusion: Chronic exercise training does not statistically affect basal blood lactate concentrations; however, it may decrease the blood lactate concentrations during exercise, indicating improvements of physical performance capacity which is beneficial for T2DM patients' health in general. Why chronic exercise training did not affect basal blood lactate concentrations needs further investigation.
Biological Functions of RBP4 and Its Relevance for Human Diseases
Authors: Steinhoff Julia S. , Lass Achim , Schupp Michael
Published: March 2021

Retinol binding protein 4 (RBP4) is a member of the lipocalin family and the major transport protein of the hydrophobic molecule retinol, also known as vitamin A, in the circulation. Expression of RBP4 is highest in the liver, where most of the body’s vitamin A reserves are stored as retinyl esters. For the mobilization of vitamin A from the liver, retinyl esters are hydrolyzed to retinol, which then binds to RBP4 in the hepatocyte. After associating with transthyretin (TTR), the retinol/RBP4/TTR complex is released into the bloodstream and delivers retinol to tissues via binding to specific membrane receptors. So far, two distinct RBP4 receptors have been identified that mediate the uptake of retinol across the cell membrane and, under specific conditions, bi-directional retinol transport. Although most of RBP4’s actions depend on its role in retinoid homeostasis, functions independent of retinol transport have been described. In this review, we summarize and discuss the recent findings on the structure, regulation, and functions of RBP4 and lay out the biological relevance of this lipocalin for human diseases.
Mediator Subunits MED16, MED14, and MED2 Are Required for Activation of ABRE-Dependent Transcription in Arabidopsis
Authors: Lee Morgan , Dominguez-Ferreras Anna , Kaliyadasa Ewon , Huang Wei-Jie , Antony Edna , Stevenson Tracey , Lehmann Silke , Schäfer Patrick , Knight Marc R. , Ntoukakis Vardis , Knight Heather
Published: March 2021

The Mediator complex controls transcription of most eukaryotic genes with individual subunits required for the control of particular gene regulons in response to various perturbations. In this study, we reveal the roles of the plant Mediator subunits MED16, MED14, and MED2 in regulating transcription in response to the phytohormone abscisic acid (ABA) and we determine which cis elements are under their control. Using synthetic promoter reporters we established an effective system for testing relationships between subunits and specific cis-acting motifs in protoplasts. Our results demonstrate that MED16, MED14, and MED2 are required for the full transcriptional activation by ABA of promoters containing both the ABRE (ABA-responsive element) and DRE (drought-responsive element). Using synthetic promoter motif concatamers, we showed that ABA-responsive activation of the ABRE but not the DRE motif was dependent on these three Mediator subunits. Furthermore, the three subunits were required for the control of water loss from leaves but played no role in ABA-dependent growth inhibition, highlighting specificity in their functions. Our results identify new roles for three Mediator subunits, provide a direct demonstration of their function and highlight that our experimental approach can be utilized to identify the function of subunits of plant transcriptional regulators.
Home Literacy and Numeracy Environments in Asia
Authors: Cheung Sum Kwing , Dulay Katrina May , Yang Xiujie , Mohseni Fateme , McBride Catherine
Published: March 2021

The home learning environment includes what parents do to stimulate children’s literacy and numeracy skills at home and their overall beliefs and attitudes about children’s learning. The home literacy and numeracy environments are two of the most widely discussed aspects of the home learning environment, and past studies have identified how socioeconomic status and parents’ own abilities and interest in these domains also play a part in shaping children’s learning experiences. However, these studies are mostly from the West, and there has been little focus on the situation of homes in Asia, which captures a large geographical area and a wide diversity of social, ethnic, and linguistic groups. Therefore, this paper aims to review extant studies on the home literacy and numeracy environments that have been conducted in different parts of Asia, such as China, the Philippines, India, Iran, Turkey, and the United Arab Emirates. Specifically, we explore how parents in these places perceive their roles in children’s early literacy and numeracy development, the methods they regard as effective for promoting young children’s literacy and numeracy learning, and the frequency with which they engage their young children in different types of home literacy and numeracy activities. We also examine studies on the relationship of the home literacy and numeracy environment with young children’s developmental outcomes, and the effectiveness of parent training programs to improve the home literacy and numeracy environments in these contexts. By examining potential trends in findings obtained in different geographical areas, we can initially determine whether there are characteristics that are potentially unique to contexts in Asia. We propose future research directions that acknowledge the role of cultural values and social factors in shaping the home learning environment, and, by extension, in facilitating children’s early literacy and numeracy development.
Positive Environments and Precautionary Behaviors During the COVID-19 Outbreak
Authors: Corral-Verdugo Víctor , Corral-Frías Nadia S. , Frías-Armenta Martha , Lucas Marc Yancy , Peña-Torres Edgar F.
Published: March 2021

Theoretically, a positive environment (PE) includes (a) tangible and intangible resources that satisfy human needs, (b) enablers of healthy, pro-social, and pro-environmental behaviors that guarantee socio-environmental quality and wellbeing, and (c) environmental challenges that must be faced and solved. One of the most salient challenges is the global COVID-19 pandemic. This study sought to investigate whether PEs can stimulate responsible actions (i.e., self-care and precautionary behaviors against COVID-19), while maintaining personal wellbeing. Nine hundred and forty-nine Mexicans participated in an online survey encompassing five primary factors: resources, enablers, challenges, responsible health behaviors, and wellbeing. The first three factors examine “resources” such as physical infrastructure as well as family and social support, “enablers” which include information about protective health practices and perceived legitimacy of authorities in handling the pandemic, and “challenges” encompassing threat perception and social pressure to not engage in precautionary measures. Participants also self-reported hedonic wellbeing as well as self-care and precautionary behaviors, which formed the “responsible (health) behavior” factor. Structural equations model (n= 714 after list-wise deletion) showed that “resources,” “challenges,” and “enablers” form a second-order factor, “positive environments,” and this factor strongly covaries with “responsible behavior” and “wellbeing.” These results suggest that PEs are not only buffers against the negative impact of the COVID-19 pandemic but can also stimulate effective responses against a threat while maintaining individual wellbeing. These results can be used to inform the development and maintenance of PE frameworks aimed at minimizing the spread of COVID-19 and encouraging mental and physical health.
Neuroimaging as a Window Into the Pathophysiological Mechanisms of Schizophrenia
Authors: Kraguljac Nina Vanessa , Lahti Adrienne Carol
Published: March 2021

Schizophrenia is a complex neuropsychiatric disorder with a diverse clinical phenotype that has a substantial personal and public health burden. To advance the mechanistic understanding of the illness, neuroimaging can be utilized to capture different aspects of brain pathologyin vivo, including brain structural integrity deficits, functional dysconnectivity, and altered neurotransmitter systems. In this review, we consider a number of key scientific questions relevant in the context of neuroimaging studies aimed at unraveling the pathophysiology of schizophrenia and take the opportunity to reflect on our progress toward advancing the mechanistic understanding of the illness. Our data is congruent with the idea that the brain is fundamentally affected in the illness, where widespread structural gray and white matter involvement, functionally abnormal cortical and subcortical information processing, and neurometabolic dysregulation are present in patients. Importantly, certain brain circuits appear preferentially affected and subtle abnormalities are already evident in first episode psychosis patients. We also demonstrated that brain circuitry alterations are clinically relevant by showing that these pathological signatures can be leveraged for predicting subsequent response to antipsychotic treatment. Interestingly, dopamine D2 receptor blockers alleviate neural abnormalities to some extent. Taken together, it is highly unlikely that the pathogenesis of schizophrenia is uniform, it is more plausible that there may be multiple different etiologies that converge to the behavioral phenotype of schizophrenia. Our data underscore that mechanistically oriented neuroimaging studies must take non-specific factors such as antipsychotic drug exposure or illness chronicity into consideration when interpreting disease signatures, as a clear characterization of primary pathophysiological processes is an imperative prerequisite for rational drug development and for alleviating disease burden in our patients.