bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct Signaling Functions of Rap1 Isoforms in NO Release From Endothelium
Authors: Kosuru Ramoji , Singh Bandana , Lakshmikanthan Sribalaji , Nishijima Yoshinori , Vasquez-Vivar Jeannette , Zhang David X. , Chrzanowska Magdalena
Published: June 2021

Small GTPase Rap1 plays a prominent role in endothelial cell (EC) homeostasis by promoting NO release. Endothelial deletion of the two highly homologous Rap1 isoforms, Rap1A and Rap1B, leads to endothelial dysfunctionex vivoand hypertensionin vivo. Mechanistically, we showed that Rap1B promotes NO release in response to shear flow by promoting mechanosensing complex formation involving VEGFR2 and Akt activation. However, the specific contribution of the Rap1A isoform to NO release and the underlying molecular mechanisms through which the two Rap1 isoforms control endothelial function are unknown. Here, we demonstrate that endothelial dysfunction resulting from knockout of both Rap1A and Rap1B isoforms is ameliorated by exogenous L-Arg administration to rescue NO-dependent vasorelaxation and blood pressure. We confirmed that Rap1B is rapidly activated in response to agonists that trigger eNOS activation, and its deletion in ECs attenuates eNOS activation, as detected by decreased Ser1177 phosphorylation. Somewhat surprising was the finding that EC deletion of Rap1A does not lead to impaired agonist-induced vasorelaxationex vivo. Mechanistically, the deletion of Rap1A led to elevated eNOS phosphorylation both at the inhibitory, T495, and the activating Ser1177 residues. These findings indicate that the two Rap1 isoforms actviadistinct signaling pathways: while Rap1B directly positively regulates eNOS activation, Rap1A prevents negative regulation of eNOS. Notably, the combined deficiency of Rap1A and Rap1B has a severe effect on eNOS activity and NO release with anin vivoimpact on endothelial function and vascular homeostasis.
IRE1-mTOR-PERK Axis Coordinates Autophagy and ER Stress-Apoptosis Induced by P2X7-Mediated Ca2+ Influx in Osteoarthritis
Authors: Li Zihao , Huang Ziyu , Zhang He , Lu Jinghan , Wei Yingliang , Yang Yue , Bai Lunhao
Published: June 2021

Moderate-intensity exercise can help delay the development of osteoarthritis (OA). Previous studies have shown that the purinergic receptor P2X ligand gated ion channel 7 (P2X7) is involved in OA development and progression. To investigate the effect of exercise on P2X7 activation and downstream signaling in OA, we used the anterior cruciate ligament transection (ACLT)-induced OA rat model and primary chondrocyte culture system. Our in vivo experiments confirmed that treadmill exercise increased P2X7 expression and that this effect was more pronounced at the later time points. Furthermore, P2X7 activation induced endoplasmic reticulum (ER) stress and increased the expression levels of ER stress markers, such as 78 kDa glucose-regulated protein (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme-1 (IRE1), and activating transcription factor 6 (ATF6). At the early time points, IRE1 and PERK were activated, and mTOR was inhibited. At the later time points, mTOR was activated, mediating PERK to promote ER stress-apoptosis, whereas IRE1 and autophagy were inhibited. To confirm our observations in vitro, we treated primary chondrocytes with the P2X7 agonist benzoylbenzoyl-ATP (Bz-ATP). Our results confirmed that P2X7-mediated Ca2+ influx activated IRE1-mediated autophagic flux and induced PERK-mediated ER stress-apoptosis. To further investigate the role of P2X7 in OA, we injected mTOR antagonist rapamycin or P2X7 antagonist A740003 into the knee joints of ACLT rats. Our results demonstrated that mTOR inhibition induced autophagy, decreased apoptosis, and reduced cartilage loss. However, injection of mTOR agonist MHY1485 or Bz-ATP had the opposite effect. In summary, our results indicated that during the early stages of moderate-intensity exercise, P2X7 was activated and autophagic flux was increased, delaying OA development. At the later stages, P2X7 became over-activated, and the number of apoptotic cells increased, promoting OA development. We propose that the IRE1-mTOR-PERK signaling axis was involved in the regulation of autophagy inhibition and the induction of apoptosis. Our findings provide novel insights into the positive and preventative effects of exercise on OA, suggesting that the intensity and duration of exercise play a critical role. We also demonstrated that on a molecular level, P2X7 and its downstream pathways could be potential therapeutic targets for OA.
Chelating Agent Functionalized Substrates for the Formation of Thick Films via Electrophoretic Deposition
Authors: Mills Sara C. , Starr Natalie E. , Bohannon Nicholas J. , Andrew Jennifer S.
Published: June 2021

Incorporating nanoparticles into devices for a wide range of applications often requires the formation of thick films, which is particularly necessary for improving magnetic power storage, microwave properties, and sensor performance. One approach to assembling nanoparticles into films is the use of electrophoretic deposition (EPD). This work seeks to develop methods to increase film thickness and stability in EPD by increasing film-substrate interactions via functionalizing conductive substrates with various chelating agents. Here, we deposited iron oxide nanoparticles onto conductive substrates functionalized with three chelating agents with different functional moieties and differing chelating strengths. We show that increasing chelating strength can increase film-substrate interactions, resulting in thicker films when compared to traditional EPD. Results will also be presented on how the chelating strength relates to film formation as a function of deposition conditions. Yield for EPD is influenced by deposition conditions including applied electric field, particle concentration, and deposition time. This work shows that the functionalization of substrates with chelating agents that coordinate strongly with nanoparticles (phosphonic acid and dopamine) overcome parameters that traditionally hinder the deposition of thicker and more stable films, such as applied electric field and high particle concentration. We show that functionalizing substrates with chelating agents is a promising method to fabricate thick, stable films of nanoparticles deposited via EPD over a larger processing space by increasing film-substrate interactions.
Diagnostic Methods for Non-Falciparum Malaria
Authors: Gimenez Alba Marina , Marques Rodolfo F. , Regiart Matías , Bargieri Daniel Youssef
Published: June 2021

Malaria is a serious public health problem that affects mostly the poorest countries in the world, killing more than 400,000 people per year, mainly children under 5 years old. Among the control and prevention strategies, the differential diagnosis of thePlasmodium–infecting species is an important factor for selecting a treatment and, consequently, for preventing the spread of the disease. One of the main difficulties for the detection of a specificPlasmodiumsp is that most of the existing methods for malaria diagnosis focus on detectingP. falciparum. Thus, in many cases, the diagnostic methods neglect the other non-falciparum species and underestimate their prevalence and severity. Traditional methods for diagnosing malaria may present low specificity or sensitivity to non-falciparum spp. Therefore, there is high demand for new alternative methods able to differentiatePlasmodiumspecies in a faster, cheaper and easier manner to execute. This review details the classical procedures and new perspectives of diagnostic methods for malaria non-falciparum differential detection and the possibilities of their application in different circumstances.
Transcriptional Studies on Trypanosoma cruzi – Host Cell Interactions: A Complex Puzzle of Variables
Authors: Libisch María Gabriela , Rego Natalia , Robello Carlos
Published: June 2021

Chagas Disease, caused by the protozoan parasite Trypanosoma cruzi, affects nearly eight million people in the world. T. cruzi is a complex taxon represented by different strains with particular characteristics, and it has the ability to infect and interact with almost any nucleated cell. The T. cruzi-host cell interactions will trigger molecular signaling cascades in the host cell that will depend on the particular cell type and T. cruzi strain, and also on many different experimental variables. In this review we collect data from multiple transcriptomic and functional studies performed in different infection models, in order to highlight key differences between works that in our opinion should be addressed when comparing and discussing results. In particular, we focus on changes in the respiratory chain and oxidative phosphorylation of host cells in response to infection, which depends on the experimental model of T. cruzi infection. Finally, we also discuss host cell responses which reiterate independently of the strain, cell type and experimental conditions.
A Novel Initialization Technique for Decadal Climate Predictions
Authors: Volpi Danila , Meccia Virna L. , Guemas Virginie , Ortega Pablo , Bilbao Roberto , Doblas-Reyes Francisco J. , Amaral Arthur , Echevarria Pablo , Mahmood Rashed , Corti Susanna
Published: June 2021

Model initialization is a matter of transferring the observed information available at the start of a forecast to the model. An optimal initialization is generally recognized to be able to improve climate predictions up to a few years ahead. However, systematic errors in models make the initialization process challenging. When the observed information is transferred to the model at the initialization time, the discrepancy between the observed and model mean climate causes the drift of the prediction toward the model-biased attractor. Although such drifts can be generally accounted for with a posteriori bias correction techniques, the bias evolving along the prediction might affect the variability that we aim at predicting, and disentangling the small magnitude of the climate signal from the initial drift to be removed represents a challenge. In this study, we present an innovative initialization technique that aims at reducing the initial drift by performing a quantile matching between the observed state at the initialization time and the model state distribution. The adjusted initial state belongs to the model attractor and the observed variability amplitude is scaled toward the model one. Multi-annual climate predictions integrated for 5 years and run with the EC-Earth3 Global Coupled Model have been initialized with this novel methodology, and their prediction skill has been compared with the non-initialized historical simulations from CMIP6 and with the same decadal prediction system but based on full-field initialization. We perform a skill assessment of the surface temperature, the heat content in the ocean upper layers, the sea level pressure, and the barotropic ocean circulation. The added value of the quantile matching initialization is shown in the North Atlantic subpolar region and over the North Pacific surface temperature as well as for the ocean heat content up to 5 years. Improvements are also found in the predictive skill of the Atlantic Meridional Overturning Circulation and the barotropic stream function in the Labrador Sea throughout the 5 forecast years when compared to the full field method.
Birth Weight and Adult Obesity Index in Relation to the Risk of Hypertension: A Prospective Cohort Study in the UK Biobank
Authors: Zhang Yi , Liang Jingjia , Liu Qian , Fan Xikang , Xu Cheng , Gu Aihua , Zhao Wei , Hang Dong
Published: June 2021

Objectives: To investigate the association between birth weight and the risk of hypertension, and to examine the interaction between birth weight and the adult obesity index.

Methods: We included 199,893 participants who had birth weight data and no history of hypertension at baseline (2006–2010) from the UK Biobank. A multivariate cubic regression spline was used to visually explore the dose-response relationship. Multivariate Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: We observed a nonlinear inverse association between birth weight and hypertension. The risk for hypertension decreased as birth weight increased up to approximately 3.80 kg. Compared with the participants with the fourth quintile of birth weight (3.43–3.80 kg), those with the first quartile of birth weight (<2.88 kg) were associated with a 25% higher risk of hypertension [HR 1.25; 95% CI (1.18–1.32)]. In addition, the participants with birth weight <2.88 kg and body mass index ≥30 kg/m2 had the highest risk [HR 3.54; 95% CI (3.16–3.97); p for interaction <0.0001], as compared with those with birth weight between 3.43–3.80 kg and body mass index between 18.5–25.0 kg/m2. These associations were largely consistent in the stratified and sensitivity analyses.

Conclusion: Our findings indicate that lower birth weight is nonlinearly correlated with higher risk of hypertension, and birth weight between 3.43–3.80 kg might represent an intervention threshold. Moreover, lower birth weight may interact with adult obesity to significantly increase hypertension risk.
Acetazolamide Improves Right Ventricular Function and Metabolic Gene Dysregulation in Experimental Pulmonary Arterial Hypertension
Authors: Spyropoulos Fotios , Michael Zoe , Finander Benjamin , Vitali Sally , Kosmas Kosmas , Zymaris Panagiotis , Kalish Brian T. , Kourembanas Stella , Christou Helen
Published: June 2021

Background: Right ventricular (RV) performance is a key determinant of mortality in pulmonary arterial hypertension (PAH). RV failure is characterized by metabolic dysregulation with unbalanced anaerobic glycolysis, oxidative phosphorylation, and fatty acid oxidation (FAO). We previously found that acetazolamide (ACTZ) treatment modulates the pulmonary inflammatory response and ameliorates experimental PAH.

Objective: To evaluate the effect of ACTZ treatment on RV function and metabolic profile in experimental PAH.

Design/Methods: In the Sugen 5416/hypoxia (SuHx) rat model of severe PAH, RV transcriptomic analysis was performed by RNA-seq, and top metabolic targets were validated by RT-PCR. We assessed the effect of therapeutic administration of ACTZ in the drinking water on hemodynamics by catheterization [right and left ventricular systolic pressure (RVSP and LVSP, respectively)] and echocardiography [pulmonary artery acceleration time (PAAT), RV wall thickness in diastole (RVWT), RV end-diastolic diameter (RVEDD), tricuspid annular plane systolic excursion (TAPSE)] and on RV hypertrophy (RVH) by Fulton's index (FI) and RV-to-body weight (BW) ratio (RV/BW). We also examined myocardial histopathology and expression of metabolic markers in RV tissues.

Results: There was a distinct transcriptomic signature of RVH in the SuHx model of PAH, with significant downregulation of metabolic enzymes involved in fatty acid transport, beta oxidation, and glucose oxidation compared to controls. Treatment with ACTZ led to a pattern of gene expression suggestive of restored metabolic balance in the RV with significantly increased beta oxidation transcripts. In addition, the FAO transcription factor peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1α) was significantly downregulated in untreated SuHx rats compared to controls, and ACTZ treatment restored its expression levels. These metabolic changes were associated with amelioration of the hemodynamic and echocardiographic markers of RVH in the ACTZ-treated SuHx animals and attenuation of cardiomyocyte hypertrophy and RV fibrosis.

Conclusion: Acetazolamide treatment prevents the development of PAH, RVH, and fibrosis in the SuHx rat model of severe PAH, improves RV function, and restores the RV metabolic profile.
Hypofunction of Circulating Endothelial Progenitor Cells and Aggravated Severity in Elderly Male Patients With Non-ST Segment Elevation Myocardial Infarction: Its Association With Systemic Inflammation
Authors: Zeng Lijin , Zhang Cong , Zhu Yuanting , Liu Zhihao , Liu Gexiu , Zhang Bin , Tu Chang , Yang Zhen
Published: June 2021

Background: Aging patients easily suffer from non-ST segment elevation myocardial infarction (NSTEMI). Our previous studies revealed declined function of endothelial progenitor cells (EPCs) in the elderly. However, the impact of aging on EPC function and severity in male NSTEMI patients and its possible mechanism is unclear until now.

Methods: We measured the circulating EPC function including migration, proliferation, and adhesion in aging or young male patients with NSTEMI. The GRACE and TIMI risk score were evaluated. Plasma levels of interleukin-6 (IL-6) and interleukin-17 (IL-17) were also detected in all patients.

Results: Compared with the young group, the old male patients with NSTEMI had higher GRACE score and TIMI score and decreased function of circulating EPCs. EPC function was negatively correlated with GRACE score and TIMI score. IL-6 and IL-17 level were higher in the old group than those in the young group. There was a significant negative correlation between EPC function and IL-6 or IL-17. Moreover, IL-6 and IL-17 positively correlated with GRACE and TIMI score. Age was positively related with GRACE or TIMI score and plasma level of IL-6 or IL-17, but inversely correlated with EPC function.

Conclusions: The current study firstly illustrates that the age-related decrement in EPC function is related to the severity of NSTEMI in male patients, which may be connected with systemic inflammation. These findings provide novel insights into the pathogenetic mechanism and intervention target of aging NSTEMI.
Digital Contact Tracing Against COVID-19 in Europe: Current Features and Ongoing Developments
Authors: Blasimme Alessandro , Ferretti Agata , Vayena Effy
Published: June 2021

The SARS-CoV-2 pandemic is a public health challenge of unprecedented scale. In the midst of the first wave of the pandemic, governments worldwide introduced digital contact tracing systems as part of a strategy to contain the spread of the virus. In Europe, after intense discussion about privacy-related risks involving policymakers, technology experts, information technology companies, and—albeit to a limited extent—the public at large, technical protocols were created to support the development of privacy-compatible proximity tracing apps. However, as the second wave of SARS-CoV-2 sweeps the continent, digital contact tracing in Europe is evolving in terms of both technological and governance features. To enable policymakers to harness the full potential of digital health tools against SARS-CoV-2, this paper examines the evolution of digital contact tracing in eight European countries. Our study highlights that while privacy and data protection are at the core of contact tracing apps in Europe, countries differ in their technical protocols, and in their capacity to utilize collected data beyond proximity tracing alone. In particular, the most recently released apps tend to offer users more granular information about risk in specific locations, and to collect data about user whereabouts, in order to enhance retrospective contact tracing capacity. These developments signal a shift from a strict interpretation of data minimization and purpose limitation toward a more expansive approach to digital contact tracing in Europe, calling for careful scrutiny and appropriate oversight.
Understanding Human Papillomavirus Vaccine Promotions and Hesitancy in Northern California Through Examining Public Facebook Pages and Groups
Authors: Zhang Jingwen , Xue Haoning , Calabrese Christopher , Chen Huiling , Dang Julie H. T.
Published: June 2021

Human papillomavirus (HPV) vaccination coverage among adolescents is lower in rural regions and remains under the 80% coverage goal by Healthy People 2030. Through both sentiment analysis and topic modeling, this research examines how local health agencies and groups in nine Northern California counties promote HPV vaccines through Facebook and how target populations react to promotion posts in comments that elucidate their sentiments and hesitancy toward HPV vaccination. In January 2021, we identified 2,105 public Facebook pages and 1,065 groups related to health within the counties and collected a total of 212 posts and 505 comments related to the HPV vaccine. The posts were published between 2010 and 2021, with the majority (83%) published after 2017. There were large variations of Facebook activities across counties. We categorized four counties with HPV vaccination initiation rates below 40% as low-coverage counties and five counties with rates above 40% as high-coverage counties. In general, low-coverage counties had fewer Facebook activities in comparison to high coverage. Results showed that, on average, comments about the HPV vaccine exhibited more positive emotion, more negative emotion, and more anger than the posts. Overall, thematic topics that emerged from posts centered around awareness and screening of HPV and cervical cancer, STI testing services, information sources, and calls to action for health services. However, comment topics did not correspond to posts and were mostly related to vaccine hesitancy, discussing vaccine risks, safety concerns, and distrust in vaccine science, citing misinformation. When comparing high- versus low-coverage counties, posts expressed similar sentiments; however, comments within high-coverage counties expressed more anger than in low-coverage counties. Comments from both high- and low-coverage counties expressed concerns with vaccine safety, risks, and injury. It is important to note that commenters exchanged information sources and tried to address misinformation themselves. Our results suggest that the promotion of HPV vaccines from public Facebook pages and groups is limited in frequency and content diversity. This illustrates problems with generalized social media vaccination promotion without community tailoring and addressing specific hesitancy concerns. Public health agencies should listen to the thoughts of targeted audiences reflected through comments and design relevant messages to address these concerns for HPV vaccination promotion.
Gut Microbiota: The Missing Link Between Helicobacter pylori Infection and Metabolic Disorders?
Authors: Martin-Nuñez Gracia M. , Cornejo-Pareja Isabel , Clemente-Postigo Mercedes , Tinahones Francisco J.
Published: June 2021

Helicobacter pylori (H. pylori) is a gram-negative bacterium that infects approximately 4.4 billion individuals worldwide. Although the majority of infected individuals remain asymptomatic, this bacterium colonizes the gastric mucosa causing the development of various clinical conditions as peptic ulcers, chronic gastritis and gastric adenocarcinomas and mucosa-associated lymphoid tissue lymphomas, but complications are not limited to gastric ones. Extradigestive pathologies, including metabolic disturbances such as diabetes, obesity and nonalcoholic fatty liver disease, have also been associated with H. pylori infection. However, the underlying mechanisms connecting H. pylori with extragastric metabolic diseases needs to be clarified. Notably, the latest studies on the topic have confirmed that H. pylori infection modulates gut microbiota in humans. Damage in the gut bacterial community (dysbiosis) has been widely related to metabolic dysregulation by affecting adiposity, host energy balance, carbohydrate metabolism, and hormonal modulation, among others. Taking into account that Type 2 diabetic patients are more prone to be H. pylori positive, gut microbiota emerges as putative key factor responsible for this interaction. In this regard, the therapy of choice for H. pylori eradication, based on proton pump inhibitor combined with two or more antibiotics, also alters gut microbiota composition, but consequences on metabolic health of the patients has been scarcely explored. Recent studies from our group showed that, despite decreasing gut bacterial diversity, conventional H. pylori eradication therapy is related to positive changes in glucose and lipid profiles. The mechanistic insights explaining these effects should also be addressed in future research. This review will deal with the role of gut microbiota as the linking factor between H. pylori infection and metabolic diseases, and discussed the impact that gut bacterial modulation by H. pylori eradication treatment can also have in host’s metabolism. For this purpose, new evidence from the latest human studies published in more recent years will be analyzed.
COVID-19 and Diabetes: Understanding the Interrelationship and Risks for a Severe Course
Authors: Landstra Cyril P. , de Koning Eelco J. P.
Published: June 2021

The relationship between COVID-19 and diabetes mellitus is complicated and bidirectional. On the one hand, diabetes mellitus is considered one of the most important risk factors for a severe course of COVID-19. Several factors that are often present in diabetes mellitus are likely to contribute to this risk, such as older age, a proinflammatory and hypercoagulable state, hyperglycemia and underlying comorbidities (hypertension, cardiovascular disease, chronic kidney disease and obesity). On the other hand, a severe COVID-19 infection, and its treatment with steroids, can have a specific negative impact on diabetes itself, leading to worsening of hyperglycemia through increased insulin resistance and reduced β-cell secretory function. Worsening hyperglycemia can, in turn, adversely affect the course of COVID-19. Although more knowledge gradually surfaces as the pandemic progresses, challenges in understanding the interrelationship between COVID-19 and diabetes remain.
Acetate Does Not Affect Palmitate Oxidation and AMPK Phosphorylation in Human Primary Skeletal Muscle Cells
Authors: González Hernández Manuel A. , Blaak Ellen E. , Hoebers Nicole T. H. , Essers Yvonne P. G. , Canfora Emanuel E. , Jocken Johan W. E.
Published: June 2021

Our recent in vivo human studies showed that colonic administration of sodium acetate (SA) resulted in increased circulating acetate levels, which was accompanied by increments in whole-body fat oxidation in overweight-obese men. Since skeletal muscle has a major role in whole-body fat oxidation, we aimed to investigate effects of SA on fat oxidation and underlying mechanisms in human primary skeletal muscle cells (HSkMC). We investigated the dose (0–5 mmol/L) and time (1, 4, 20, and 24 h) effect of SA on complete and incomplete endogenous and exogenous oxidation of 14C-labeled palmitate in HSkMC derived from a lean insulin sensitive male donor. Both physiological (0.1 and 0.25 mmol/L) and supraphysiological (0.5, 1 and 5 mmol/L) concentrations of SA neither increased endogenous nor exogenous fat oxidation over time in HSkMC. In addition, no effect of SA was observed on Thr172-AMPKα phosphorylation. In conclusion, our previously observed in vivo effects of SA on whole-body fat oxidation in men may not be explained via direct effects on HSkMC fat oxidation. Nevertheless, SA-mediated effects on whole-body fat oxidation may be triggered by other mechanisms including gut-derived hormones or may occur in other metabolically active tissues.
Mutational Landscape of the Proglucagon-Derived Peptides
Authors: Lindquist Peter , Madsen Jakob S. , Bräuner-Osborne Hans , Rosenkilde Mette M. , Hauser Alexander S.
Published: June 2021

Strong efforts have been placed on understanding the physiological roles and therapeutic potential of the proglucagon peptide hormones including glucagon, GLP-1 and GLP-2. However, little is known about the extent and magnitude of variability in the amino acid composition of the proglucagon precursor and its mature peptides. Here, we identified 184 unique missense variants in the human proglucagon gene GCG obtained from exome and whole-genome sequencing of more than 450,000 individuals across diverse sub-populations. This provides an unprecedented source of population-wide genetic variation data on missense mutations and insights into the evolutionary constraint spectrum of proglucagon-derived peptides. We show that the stereotypical peptides glucagon, GLP-1 and GLP-2 display fewer evolutionary alterations and are more likely to be functionally affected by genetic variation compared to the rest of the gene products. Elucidating the spectrum of genetic variations and estimating the impact of how a peptide variant may influence human physiology and pathophysiology through changes in ligand binding and/or receptor signalling, are vital and serve as the first important step in understanding variability in glucose homeostasis, amino acid metabolism, intestinal epithelial growth, bone strength, appetite regulation, and other key physiological parameters controlled by these hormones.
Impact of Large-Scale Mobile Electric Vehicle Charging in Smart Grids: A Reliability Perspective
Authors: Xue Ping , Xiang Yue , Gou Jing , Xu Weiting , Sun Wei , Jiang Zhuozhen , Jawad Shafqat , Zhao Huangjiang , Liu Junyong
Published: June 2021

The charging load of electric vehicles (EVs) is characterized by uncertainty and flexibility, which burdens the distribution network, especially when there is a high penetration of distributed generation (DG) in smart grids. Large-scale EV mobility integration not only affects smart grid operation reliability but also the reliability of EV charging services. This paper aims at estimating the comprehensive impacts caused by spatial-temporal EV charging from the perspective of both electricity system reliability and EV charging service reliability. First, a comprehensive reliability index system, including two novel indexes quantifying EV charging service reliability, is proposed. Then, considering traffic constraints and users’ charging willingness, a spatial-temporal charging load model is introduced. In the coupled transportation and grid framework, the reliability impacts from plenty of operation factors are analyzed. Moreover, the electricity system reliability and EV charging service reliability correlated with DG integration are discussed. A coupled transportation grid system is adopted to demonstrate the effectiveness and practicability of the proposed method. The numerical results analyze reliability impacts from EV penetration level, trip chain, EV battery capacity, DG installation location, and capacity. The proposed studies reveal that when the EV capacity ratio to DG capacity is 3:1, the system reliability reaches the maximum level.
Physiomorphic Transformation in Extreme Endurance Migrants: Revisiting the Case of Bar-Tailed Godwits Preparing for Trans-Pacific Flights
Authors: Piersma Theunis , Gill Robert E. , Ruthrauff Daniel R.
Published: June 2021

In a 1998 paper entitled “Guts don’t fly: small digestive organs in obese bar-tailed godwits,”Piersma and Gill (1998)showed that the digestive organs were tiny and the fat loads huge in individuals suspected of embarking on a non-stop flight from Alaska to New Zealand. It was suggested that prior to migratory departure, these godwits would shrink the digestive organs used during fuel deposition and boost the size and capacity of exercise organs to optimize flight performance. Here we document the verity of the proposed physiomorphic changes by comparing organ sizes and body composition of bar-tailed godwitsLimosa lapponica bauericollected in modesty midway during their fueling period (mid-September; fueling,n= 7) with the previously published data for godwits that had just departed on their trans-Pacific flight (October 19; flying,n= 9). Mean total body masses for the two groups were nearly identical, but nearly half of the body mass of fueling godwits consisted of water, while fat constituted over half of total body mass of flying godwits. The two groups also differed in their fat-free mass components. The heart and flight muscles were heavier in fueling godwits, but these body components constituted a relatively greater fraction of the fat-free mass in flying godwits. In contrast, organs related to digestion and homeostasis were heavier in fueling godwits, and most of these organ groups were also relatively larger in fueling godwits compared to flying godwits. These results reflect the functional importance of organ and muscle groups related to energy acquisition in fueling godwits and the consequences of flight-related exertion in flying godwits. The extreme physiomorphic changes apparently occurred over a short time window (≤1 month). We conclude that the inferences made on the basis of the 1998 paper were correct. The cues and stimuli which moderate these changes remain to be studied.
Genetic Variants and Functional Analyses of the ATG16L1 Gene Promoter in Acute Myocardial Infarction
Authors: Han Falan , Pang Shuchao , Sun Zhaoqing , Cui Yinghua , Yan Bo
Published: June 2021

Background

Acute myocardial infarction (AMI), a common complex disease caused by an interaction between genetic and environmental factors, is a serious type of coronary artery disease and is also a leading cause of death worldwide. Autophagy-related 16-like 1 (ATG16L1) is a key regulatory factor of autophagy and plays an important role in induced autophagy. In the cardiovascular system, autophagy is essential to preserve the homeostasis and function of the heart and blood vessels. No studies have hitherto examined the association between AMI and ATG16L1 gene promoter.

Methods

We conducted a case-control study, using polymerase chain reaction and sequencing techniques, dual luciferase reporter assay, and electrophoretic mobility shift assay, to analyze genetic and functional variation in the ATG16L1 gene promoter between AMI and controls. A variety of statistical analyses were used to analyze the allele and genotype frequencies and the relationship between single-nucleotide polymorphisms (SNPs) and AMI.

Results

In all, 10 SNPs and two DNA-sequence variants (DSVs) were identified in 688 subjects, and three ATG16L1 gene promoter mutations [g.233250693 T > C (rs185213911), g.233250946 G > A (rs568956599), g.233251133 C > G (rs1301744254)] that were identified in AMI patients significantly altered the transcriptional activity of ATG16L1 gene promoter in HEH2, HEK-293, and H9c2 cells (P < 0.05). Further electrophoretic mobility shift assays indicated that the SNPs affected the binding of transcription factors (P < 0.01).

Conclusion

ATG16L1 gene promoter mutations in AMI patients may affect the binding of transcription factors and change the transcriptional activity of the ATG16L1 gene, changing the level of autophagy and contributing to the occurrence and development of AMI as rare and low-frequency risk factors.
Comparison of the Clinical Value of miRNAs and Conventional Biomarkers in AMI: A Systematic Review
Authors: Wang Baofu , Li Yang , Hao Xuezeng , Yang Jingjing , Han Xiaowan , Li Haiyan , Li Tong , Wang Dayang , Teng Yu , Ma Liang , Li Yao , Zhao Mingjing , Wang Xian
Published: June 2021

Background/Aims:This study aimed to compare the clinical value of the peak time point and area under the curve (AUC) of miRNAs and conventional biomarkers in acute myocardial infarction (AMI).

Methods:A literature search was carried out in PubMed, Web of Science, Embase, and Cochrane systematically. Screening studies, extracting data, and assessing article quality were performed independently by two researchers. Also, the names of miRNAs in the included studies were standardized by the miRBase database.

Results:A total of 40 studies, encompassing 6,960 participants, were included in this systematic review. The samples of circulating miRNAs were mainly from the plasma. The results of this systematic review displayed that miR-1-3p, miR-19b-3p, miR-22-5p, miR-122-5p, miR-124-3p, miR-133a/b, miR-134-5p, miR-150-5p, miR-186-5p, miR-208a, miR-223-3p, miR-483-5p, and miR-499a-5p reached peak time earlier and showed a shorter time window than the conventional biomarkers despite the different collection times of initial blood samples. miR-1-3p, miR-19b-3p, miR-133a/b, miR-208a/b, miR-223-3p, miR-483-5p, and miR-499a-5p were shown to be more valuable than classical biomarkers for the early diagnosis of AMI, and these miRNAs appeared to have the most potential biomarkers within 4 h of the onset of symptoms except miR-133a/b and miR-208b. Moreover, combined miRNAs or miRNAs combined with classical biomarkers could compensate for the deficiency of single miRNA and conventional biomarker in sensitivity or specificity for an optimal clinical value.

Conclusions:miR-1-3p, miR-19b-3p, miR-208a, miR-223-3p, miR-483-5p, and miR-499a-5p are promising biomarkers for AMI due to their satisfactory diagnostic accuracy and short time window (within 4 h of the onset of symptoms).
Exclusion, Minimization, Inaction: A Critical Review of Ireland's Policy Response to Gender-Based Violence as It Affects Migrant Women
Authors: Reilly Niamh , Sahraoui Nina , McGarry Orla
Published: June 2021

This critical review of Ireland's policy response to gender-based violence as it affects migrant women contributes to recent literature that focuses on how states' legal and policy regimes can be part of the problem, in this case adding to rather than reducing GBV related vulnerabilities experienced by migrant women. Through a review of key policy, law and NGO documents, the report foregrounds the significance of context-specific framing and interpretation of influential ideas in shaping the horizons of possible policy action. The review is contextualized in relation to developments in Ireland concerning migration, citizenship and racialisation and more broadly vis-a-vis the nexus of migration governance and gender based violence. The authors trace the development of dominant ideas that shape policy practice with a focus on their interpretation in the Irish context—namely, vulnerability, intersectionality, and interculturalism. Four particular areas of policy response are identified, which reveal a pattern of policy failure on the part of the Irish state characterized by exclusion, minimization, and/or inaction. These relate to assessment of vulnerability of applicants for international protection; addressing gender-based violence in the context of direct provision accommodation; identification and referral of trafficking victims; and response to domestic violence linked to dependent migration status. The authors find that the pattern of failure identified is linked to the current dominance of an ever narrowing and individualized framing of vulnerability found in EU migration regulations, a lack of application of an intersectional gender perspective, the diminished influence of indivisible human rights norms requiring attention to economic, social and cultural rights, as a well as a wider national context of declining resource allocation to addressing gender-based violence and integration, including anti-racism initiatives, for over a decade.
Driving β2- While Suppressing α-Adrenergic Receptor Activity Suppresses Joint Pathology in Inflammatory Arthritis
Authors: Bellinger Denise L. , Wood Carlo , Wergedal Jon E. , Lorton Dianne
Published: June 2021

Objective

Hypersympathetic activity is prominent in rheumatoid arthritis, and major life stressors precede onset in ~80% of patients. These findings and others support a link between stress, the sympathetic nervous system and disease onset and progression. Here, we extend previous research by evaluating how selective peripherally acting α/β2-adrenergic drugs affect joint destruction in adjuvant-induced arthritis.

Methods

Complete Freund’s adjuvant induced inflammatory arthritis in male Lewis rats. Controls received no treatment. Arthritic rats then received vehicle or twice-daily treatment with the α-adrenergic antagonist, phentolamine (0.5 mg/day) and the β2-adrenergic agonist, terbutaline (1200 µg/day, collectively named SH1293) from day (D) of disease onset (D12) through acute (D21) and severe disease (D28). Disease progression was assessed in the hind limbs using dorsoplantar widths, X-ray analysis, micro-computed tomography, and routine histology on D14, D21, and D28 post-immunization.

Results

On D21, SH1293 significantly attenuated arthritis in the hind limbs, based on reduced lymphocytic infiltration, preservation of cartilage, and bone volume. Pannus formation and sympathetic nerve loss were not affected by SH1293. Bone area and osteoclast number revealed high- and low-treatment-responding groups. In high-responding rats, treatment with SH1293 significantly preserved bone area and decreased osteoclast number, data that correlated with drug-mediated joint preservation. SH1293 suppressed abnormal bone formation based on reduced production of osteophytes. On D28, the arthritic sparing effects of SH1293 on lymphocytic infiltration, cartilage and bone sparing were maintained at the expense of bone marrow adipocity. However, sympathetic nerves were retracted from the talocrural joint.

Conclusion and Significance

Our findings support a significant delay in early arthritis progression by treatment with SH1293. Targeting sympathetic neurotransmission may provide a strategy to slow disease progression.
The Antigenicity of Epidemic SARS-CoV-2 Variants in the United Kingdom
Authors: Wu Jiajing , Zhang Li , Zhang Yue , Wang Haixin , Ding Ruxia , Nie Jianhui , Li Qianqian , Liu Shuo , Yu Yongxin , Yang Xiaoming , Duan Kai , Qu Xiaowang , Wang Youchun , Huang Weijin
Published: June 2021

To determine whether the neutralization activity of monoclonal antibodies, convalescent sera and vaccine-elicited sera was affected by the top five epidemic SARS-CoV-2 variants in the UK, including D614G+L18F+A222V, D614G+A222V, D614G+S477N, VOC-202012/01(B.1.1.7) and D614G+69-70del+N439K, a pseudovirus-neutralization assay was performed to evaluate the relative neutralization titers against the five SARS-CoV-2 variants and 12 single deconvolution mutants based on the variants. In this study, 18 monoclonal antibodies, 10 sera from convalescent COVID-19 patients, 10 inactivated-virus vaccine-elicited sera, 14 mRNA vaccine-elicited sera, nine RBD-immunized mouse sera, four RBD-immunized horse sera, and four spike-encoding DNA-immunized guinea pig sera were tested and analyzed. The N501Y, N439K, and S477N mutations caused immune escape from nine of 18 mAbs. However, the convalescent sera, inactivated virus vaccine-elicited sera, mRNA vaccine-elicited sera, spike DNA-elicited sera, and recombinant RBD protein-elicited sera could still neutralize these variants (within three-fold changes compared to the reference D614G variant). The neutralizing antibody responses to different types of vaccines were different, whereby the response to inactivated-virus vaccine was similar to the convalescent sera.
Relationships Matter: Assessing the Impacts of a Marine Protected Area on Human Wellbeing and Relational Values in Southern Tanzania
Authors: Baker Dana , Murray Grant , Kaijage Jackson , Levine Arielle , Gill David , Makupa Enock
Published: June 2021

The push to meet global marine conservation targets has significantly increased the scope and scale of marine protected areas (MPAs) worldwide. While the benefits derived from MPA establishment are often optimistically framed as a “win-win” for both marine biodiversity and for the wellbeing of coastal peoples, this assumption is challenged for several reasons, including the fact that current science and practice frequently fails to account for the full impact of MPAs on human wellbeing. This context poses a danger that the context specific, place based aspects of wellbeing, like relations to others and the marine environment, will not be accounted for, examined, or reported in evaluation and decision-making processes. To address this challenge, this research investigates how MPA implementation can change and challenge the relational wellbeing and relational values of small-scale fishers (SSFs) living in Mnazi Bay-Ruvuma Estuary Marine Park, Tanzania. Fieldwork occurred over 2019–2020 and used qualitative data collection methods, including: 140 semi-structured interviews, document analysis, and observation. Results highlight a dynamic interaction between the MPA and SSFs relational wellbeing, including how relational values inform everyday fishing practices, cultural and place identities, as well as interactions with others and connections to the marine environment. Top-down approaches used in MPA development worked against key relational values, including social cohesion, reciprocity, place, agency and self-determination to dismantle and disrupt the practices SSFs viewed as fundamental to their livelihood and collective wellbeing. Our findings serve as a starting point to better recognize the context specific factors that underlie relational wellbeing and give insight into how relational values shape social-ecological complexity within coastal communities. The paper highlights how the international marine conservation community can better account for and foster relational wellbeing and relational values to achieve the goals of both human wellbeing and marine biodiversity conservation.
Microstructure Evolution and Shear Property of Cu-In Transient Liquid Phase Sintering Joints
Authors: Jiang Bang , Zhang Qiaoxin , Shi Lin , Zhu Chundong , Chen Zhiwen , Liu Li , Shi Yan
Published: June 2021

Transient liquid phase sintering (TLPS) is a promising joining technology that can achieve high temperature resistant solder joints at low temperature, showing excellent potential in power electronics. In this work, Cu/Cu-In/Cu solder joints were successfully prepared by TLPS process. The effects of bonding pressure and holding time on the microstructure and shear strength of Cu-In TLPS joints at 260 and 320°C were studied. The results showed that as bonding pressure increased from 0.1–0.6 MPa, the porosity decreased and shear strength increased significantly. No obvious change was found as bonding pressure continued to increase to 1 MPa. As holding time increased at 260°C, Cu11In9 was formed and gradually transformed to Cu2In that can withstand elevated temperature. Meanwhile, the porosity decreased while shear strength increased. It was calculated that volume expansion (12.74%) occurred during the phase transition from Cu11In9 to Cu2In. When bonding temperature increased to 320°C, only Cu2In was detected and then gradually transformed to Cu7In3 with the growing holding time. As holding time reached 120 min, their porosity increased and lead to weak shear strength due to volume shrinkage (15.43%) during the phase transition from Cu2In to Cu7In3.
Long Circulation of PEG-TRAIL Improves Anti-Hepatic Fibrosis Effect of TRAIL Via Targeting Activated Hepatic Stellate Cells
Authors: Lu Bingyun , Peng Lijun , Luo Shenggen , Zhou Jing’e , Xu Nan , Dong Chunxiu , Yan Zhiqiang , Li Huiyi , Li Qinghua
Published: June 2021

Background: The short half-life of TRAIL (tumor necrosis factor–related apoptosis-inducing ligand) greatly limits its clinical application. This study was aimed to improve its potency on liver fibrosis through PEG (polyethylene glycol) modification prolonging the half-life of TRAIL.

Methods: PEG, TRAIL, and the chemically synthesized complex PEG-TRAIL were used to treat 3T3 and LX-2 cells and liver fibrotic mice. In vitro, cell viability, apoptosis, and fibrosis were investigated using CCK-8 (cell counting kit-8) assay, flow cytometry, and Western blotting, respectively. In vivo, Sirius red staining, immunohistochemistry, and α-SMA (α-smooth muscle actin)/TUNEL (terminal deoxynucleotidyl transferase dUTP [2'-deoxyuridine 5'-triphosphate] nick end labeling) double-labeling immunofluorescence (IF) were performed after various treatments for liver fibrotic mice. The fibrotic liver was subjected to DR4 (death receptor 4)/TRAIL double-labeling IF to assess the retention of TRAIL enhanced by PEGylation.

Results: The cells treated with PEG-TRAIL showed lower cell viability, higher apoptosis level, and stronger anti-fibrotic effect compared with PEG or TRAIL treatment. In vivo, PEGylated TRAIL exhibited a longer circulation than TRAIL did. Compared with TRAIL treatment, PEG-TRAIL caused a significant reduction of α-SMA and a markedly increase of apoptotic aHSCs. PEGylation is more likely to prolong the retention of TRAIL in circulation and enhance the possibility to target aHSCs and DR4-positive (DR4+) cells in the liver.

Conclusion: PEG-TRAIL presents better anti-fibrotic and proapoptotic effects, for which, the prolonged circulation half-life in vivo may account. The PEG-TRAIL may serve as a new clinical therapeutic for liver fibrosis in the future.