bluuebunny/crossref_metadata_2025 huggingface dataset:
Seat Safety and Female (Under)representation in the U.S. Congress
Authors: Rajan Akhil , Kustov Alexander , Cerda Maikol , Rosenbluth Frances , Shapiro Ian
Published: May 2021

Women have made significant strides toward equal representation within the U.S. Congress, but their seat share has mostly increased within the Democratic—but not Republican—Party. We argue that one driver of women’s underrepresentation among Republicans is the proliferation of safe seats. Because safe seats encourage ideological extremism in candidates and because women are stereotyped as more liberal than men, we expect women candidates to outperform men in safer Democratic seats but underperform men in safer Republican seats (relative to more competitive seats). Based on a new dataset linking all candidates for the U.S. House and their districts’ partisan composition since 2000, we show women both enter and win elections in safer Republican (Democratic) seats at relatively lower (higher) rates than men. Our results strikingly suggest that, even conditional on running, a female Republican candidate has an overall better chance of winning in a competitive seat than in a safe Republican seat.
Dynamic Analysis of the Traffic of Vehicles Used in Car Sharing
Authors: Sergeev Sergey , Bozhuk Svetlana , Pletneva Natalia , Evdokimov Konstantin , Klochkov Yury
Published: May 2021

During digitalization of transport service segment people use modern facilities such as geolocation, M2M connectivity, online payments, customer identification. We can also see a high competition here. The task of car sharing managers is to search for the optimal methods of doing business. As the regulations of business, ecological standards and technology environment of the main players is almost similar because of using the same mobile and cloud resources, it is possible to get a competitive advantage by the development of mobile apps for the employee’s PCs and smartphones of customers. The math model shown in this article is developed for implementing in digital platforms of such kind of business. This gives the opportunity to offer customers more attractive car sharing services and to reduce costs by following the environmental restrictions at the same time.
Prolyl Endopeptidase Gene Disruption Improves Gut Dysbiosis and Non-alcoholic Fatty Liver Disease in Mice Induced by a High-Fat Diet
Authors: Jiang Daixi , Zhang Jianbin , Lin Shuangzhe , Wang Yuqin , Chen Yuanwen , Fan Jiangao
Published: May 2021

The gut-liver axis is increasingly recognized as being involved in the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD). Prolyl endopeptidase (PREP) plays a role in gut metabolic homeostasis and neurodegenerative diseases. We investigated the role of PREP disruption in the crosstalk between gut flora and hepatic steatosis or inflammation in mice with NAFLD. Wild-type mice (WT) and PREP gene knocked mice (PREPgt) were fed a low-fat diet (LFD) or high-fat diet (HFD) for 16 or 24 weeks. Murine gut microbiota profiles were generated at 16 or 24 weeks. Liver lipogenesis-associated molecules and their upstream mediators, AMP-activated protein kinase (AMPK) and sirtuin1 (SIRT1), were detected using RT-PCR or western blot in all mice. Inflammatory triggers and mediators from the gut or infiltrated inflammatory cells and signal mediators, such as p-ERK and p-p65, were determined. We found that PREP disruption modulated microbiota composition and altered the abundance of several beneficial bacteria such as the butyrate-producing bacteria in mice fed a HFD for 16 or 24 weeks. The level of butyrate in HFD-PREPgt mice significantly increased compared with that of the HFD-WT mice at 16 weeks. Interestingly, PREP disruption inhibited p-ERK and p-p65 and reduced the levels of proinflammatory cytokines in response to endotoxin and proline-glycine-proline, which guided macrophage/neutrophil infiltration in mice fed a HFD for 24 weeks. However, at 16 weeks, PREP disruption, other than regulating hepatic inflammation, displayed improved liver lipogenesis and AMPK/SIRT1 signaling. PREP disruption may target multiple hepatic mechanisms related to the liver, gut, and microbiota, displaying a dynamic role in hepatic steatosis and inflammation during NAFLD. PREP might serve as a therapeutic target for NAFLD.
An Updated Staging System for Cephalochordate Development: One Table Suits Them All
Authors: Carvalho João E. , Lahaye François , Yong Luok Wen , Croce Jenifer C. , Escrivá Hector , Yu Jr-Kai , Schubert Michael
Published: May 2021

Chordates are divided into three subphyla: Vertebrata, Tunicata, and Cephalochordata. Phylogenetically, the Cephalochordata, more commonly known as lancelets or amphioxus, constitute the sister group of Vertebrata and Tunicata. Lancelets are small, benthic, marine filter feeders, and their roughly three dozen described species are divided into three genera: Branchiostoma, Epigonichthys, and Asymmetron. Due to their phylogenetic position and their stereotypical chordate morphology and genome architecture, lancelets are key models for understanding the evolutionary history of chordates. Lancelets have thus been studied by generations of scientists, with the first descriptions of adult anatomy and developmental morphology dating back to the 19th century. Today, several different lancelet species are used as laboratory models, predominantly for developmental, molecular and genomic studies. Surprisingly, however, a universal staging system and an unambiguous nomenclature for developing lancelets have not yet been adopted by the scientific community. In this work, we characterized the development of the European lancelet (Branchiostoma lanceolatum) using confocal microscopy and compiled a streamlined developmental staging system, from fertilization through larval life, including an unambiguous stage nomenclature. By tracing growth curves of the European lancelet reared at different temperatures, we were able to show that our staging system permitted an easy conversion of any developmental time into a specific stage name. Furthermore, comparisons of embryos and larvae from the European lancelet (B. lanceolatum), the Florida lancelet (Branchiostoma floridae), two Asian lancelets (Branchiostoma belcheri and Branchiostoma japonicum), and the Bahamas lancelet (Asymmetron lucayanum) demonstrated that our staging system could readily be applied to other lancelet species. Although the detailed staging description was carried out on developing B. lanceolatum, the comparisons with other lancelet species thus strongly suggested that both staging and nomenclature are applicable to all extant lancelets. We conclude that this description of embryonic and larval development will be of great use for the scientific community and that it should be adopted as the new standard for defining and naming developing lancelets. More generally, we anticipate that this work will facilitate future studies comparing representatives from different chordate lineages.
Boosting Anion Transport Activity of Diamidocarbazoles by Electron Withdrawing Substituents
Authors: Maslowska-Jarzyna Krystyna , Korczak Maria L. , Chmielewski Michał J.
Published: May 2021

Artificial chloride transporters have been intensely investigated in view of their potential medicinal applications. Recently, we have established 1,8-diamidocarbazoles as a versatile platform for the development of active chloride carriers. In the present contribution, we investigate the influence of various electron-withdrawing substituents in positions 3 and 6 of the carbazole core on the chloride transport activity of these anionophores. Using lucigenin assay and large unilamellar vesicles as models, the 3,6-dicyano- and 3,6-dinitro- substituted receptors were found to be highly active and perfectly deliverable chloride transporters, with EC50,270s value as low as 22 nM for the Cl−/NO3− exchange. Mechanistic studies revealed that diamidocarbazoles form 1:1 complexes with chloride in lipid bilayers and facilitate chloride/nitrate exchange by carrier mechanism. Furthermore, owing to its increased acidity, the 3,6-dinitro- substituted receptor acts as a pH-switchable transporter, with physiologically relevant apparent pKa of 6.4.
Solution-Processed Pure Blue Thermally Activated Delayed Fluorescence Emitter Organic Light-Emitting Diodes With Narrowband Emission
Authors: Xu Ting , Liang Xiao , Xie Guohua
Published: May 2021

There is a need to satisfy the high color purity requirement of display technology with a simply fabricated process. Herein, solution-processed blue thermally activated delayed fluorescence organic light-emitting diodes (OLEDs) with a narrow spectrum with a full width at half maximum (FWHM) of 32 nm and y color coordinate below 0.2 are demonstrated by employing a molecule containing boron and nitrogen atoms (TBN-TPA) as the guest emitter in the emissive layer. The opposite resonance positions of B-N atoms of TBN-TPA endows a multi-resonance effect, leading to high color purity.
RT-qPCR Assays for Rapid Detection of the N501Y, 69-70del, K417N, and E484K SARS-CoV-2 Mutations: A Screening Strategy to Identify Variants With Clinical Impact
Authors: Vega-Magaña Natali , Sánchez-Sánchez Rocío , Hernández-Bello Jorge , Venancio-Landeros Alberto Antony , Peña-Rodríguez Marcela , Vega-Zepeda Rosa Alejandra , Galindo-Ornelas Byron , Díaz-Sánchez Mauricio , García-Chagollán Mariel , Macedo-Ojeda Gabriela , García-González Octavio Patricio , Muñoz-Valle José Francisco
Published: May 2021

Background

Several variants of the SARS-CoV-2 have been documented globally during the current COVID-19 pandemic. The N501Y, 69-70del, K417N, and E484K SARS-CoV-2 mutations have been documented among the most relevant due to their potential pathogenic biological effects. This study aimed to design, validate, and propose a fast real-time RT-qPCR assay to detect SARS-CoV-2 mutations with possible clinical and epidemiological relevance in the Mexican population.

Methods

Targeting spike (S) gene mutations of SARS-CoV-2 (N501Y, 69-70del, K417N, and E484K), specific primers, and probes for three specific quantitative reverse transcription PCR (RT-qPCR) assays were designed, and validated using Sanger sequencing. These assays were applied in clinical samples of 1060 COVID-19 patients from Jalisco Mexico.

Results

In silico analyzes showed high specificity of the three assays. Amplicons of samples were confirmed through sequencing. The screening of samples of COVID-19 patients allowed the identification of the E484K mutation in nine individuals and the identification of P.2 Brazilian variant in Mexico.

Conclusion

This work provides low-cost RT-qPCR assays for rapid screening and molecular surveillance of mutations with potential clinical impact. This strategy allowed the detection of E484K mutation and P.2 variant for the first time in samples from the Mexican population.
A Brief History in Cardiac Regeneration, and How the Extra Cellular Matrix May Turn the Tide
Authors: van der Pol Atze , Bouten Carlijn V. C.
Published: May 2021

Tissue homeostasis is perturbed by stressful events, which can lead to organ dysfunction and failure. This is particularly true for the heart, where injury resulting from myocardial infarction or ischemic heart disease can result in a cascading event ultimately ending with the loss of functional myocardial tissue and heart failure. To help reverse this loss of healthy contractile tissue, researchers have spent decades in the hopes of characterizing a cell source capable of regenerating the injured heart. Unfortunately, these strategies have proven to be ineffective. With the goal of truly understanding cardiac regeneration, researchers have focused on the innate regenerative abilities of zebrafish and neonatal mammals. This has led to the realization that although cells play an important role in the repair of the diseased myocardium, inducing cardiac regeneration may instead lie in the composition of the extra cellular milieu, specifically the extra cellular matrix. In this review we will briefly summarize the current knowledge regarding cell sources used for cardiac regenerative approaches, since these have been extensively reviewed elsewhere. More importantly, by revisiting innate cardiac regeneration observed in zebrafish and neonatal mammals, we will stress the importance the extra cellular matrix has on reactivating this potential in the adult myocardium. Finally, we will address how we can harness the ability of the extra cellular matrix to guide cardiac repair thereby setting the stage of next generation regenerative strategies.
Hydrophilic or Lipophilic Statins?
Authors: Climent Elisenda , Benaiges David , Pedro-Botet Juan
Published: May 2021

Drugs can be classified as hydrophilic or lipophilic depending on their ability to dissolve in water or in lipid-containing media. The predominantly lipophilic statins (simvastatin, fluvastatin, pitavastatin, lovastatin and atorvastatin) can easily enter cells, whereas hydrophilic statins (rosuvastatin and pravastatin) present greater hepatoselectivity. Although the beneficial role of statins in primary and secondary cardiovascular prevention has been unequivocally confirmed, the possible superiority of one statin or other regarding their solubility profile is still not well-established. In this respect, although some previously published observational studies and clinical trials observed a superiority of lipophilic statins in cardiovascular outcomes, these results could also be explained by a greater low-density lipoprotein cholesterol reduction with this statin type. On the other hand, previous studies reported conflicting results as to the possible superiority of one statin type over the other regarding heart failure outcomes. Furthermore, adverse events with statin therapy may also be related to their solubility profile. Thus, the aim of the present review was to collect clinical evidence on possible differences in cardiovascular outcomes among statins when their solubility profile is considered, and how this may also be related to the occurrence of statin-related adverse effects.
Geochemical and Petrographic Characterization of Marine-Continental Transitional Facies Shale (Qilian Basin, China): Origin of Organic Matter Input, Depositional Environments and Hydrocarbon Generation Potential
Authors: Wang Guocang , Sun Minzhuo , Yi Zongwang , Zhou Li , Ye Jie , Tan Heyong
Published: May 2021

This study, for the first time, investigates the source, keroger pattern, evolution degree, sedimentary environment, and evaluates the hydrocarbon generating ability of marine-continental transitional facies shale from the Ebao area of the Qilian Basin in western China. The organic-rich shales of the marine-continental transitional facies were subjected to total organic carbon (TOC), rock pyrolysis, the biomarkers and kerogen microscopy analyses. The kerogen microscopy analyses indicated that the sample from ZK001 well and ZK2002 well had a mass of vitrinite and small number of exinite, so kerogen type was mainly humic. According to vitrinite reflectance, the organic matter was in the stage of maturity to high maturity. The organic analyses indicated that the shale samples possessed the features of the higher TOC and a mixed of terrestrial and marine sources and maturity to high maturity. These features were compatible with the characterized of kerogen microscopy characteristics. A lot of organic materials in the studied shales form ZK001 well and ZK2002 well could be because there were fine protection under salt lake facies and hypoxic marine environment. Therefore, the studied shales of marine-continental transitional facies shale had very good hydrocarbon generating ability as a result of the existence of a lot of high maturity organic materials of humic.
Lake Inflow Simulation Using the Coupled Water Balance Method and Xin’anjiang Model in an Ungauged Stream of Chaohu Lake Basin, China
Authors: Li Zijun , Lei Xiaohui , Liao Weihong , Yang Qingchun , Cai Siyu , Wang Xiaoying , Wang Chao , Wang Jia
Published: May 2021

Water resources are crucial for maintaining daily life and a healthy ecological environment. In order to gain a harmonious development among water resources and economic development in Lake Watershed, it is urgent to quantify the lake inflow. However, the calculation of inflow simulations is severely limited by the lack of information regarding river runoff. This paper attempts calculated inflow in an ungauged stream through use of the coupling water balance method and the Xin’anjiang model, applying it to calculate the inflow in the Chaohu Lake Basin, China. Results show that the coupled model has been proved to be robust in determining inflow in an ungauged stream. The error of daily inflow calculated by the water balance method is between 1.4 and −19.5%, which is within the standard error range (±20%). The calibration and verification results of the coupled model suggest that the simulation results are best in the high inflow year (2016), followed by the normal inflow year (2007) and the low inflow year (1978). The Nash-Sutcliffe efficiencies for high inflow year, normal inflow year, and low inflow year are 0.82, 0.72, and 0.63, respectively, all of which have reached a satisfactory level. Further, the annual lake inflow simulation in the normal inflow year is 19.4 × 108 m3, while the annual average land surface runoff of the study area is 18.9 × 108 m3, and the relative error is −2.6% by the two ways. These results of the coupled model offer a new way to calculate the inflow in lake/reservoir basins.
Use of Local Seismic Network in Analysis of Volcano-Tectonic (VT) Events Preceding the 2017 Agung Volcano Eruption (Bali, Indonesia)
Authors: Sahara David P. , Rahsetyo Puput P. , Nugraha Andri Dian , Syahbana Devy Kamil , Widiyantoro Sri , Zulfakriza Zulfakriza , Ardianto Ardianto , Baskara Aria W. , Rosalia Shindy , Martanto Martanto , Afif Haunan
Published: May 2021

This study provides an attempt to analyze the pre-eruptive seismicity events for volcano eruption forecasting. After more than 50 years of slumber, Agung volcano on Bali Island erupted explosively, starting on November 21, 2017. The eruption was preceded by almost 2 months of significant increase of recorded seismicity, herein defined as “seismic crisis.” Our study provides the first analysis of VT events using data from eight local seismic stations deployed by the Center for Volcanology and Geological Hazard Mitigation of Indonesia (CVGHM) to monitor the Agung Volcano activity. In total, 2,726 Volcano-Tectonic (VT) events, with 13,023 P waves and 11,823 S wave phases, were successfully identified between October 18 and November 30, 2017. We increased the accuracy of the hypocenter locations of these VT events using a double-difference (DD) relative relocation and a new velocity model appropriate to the subsurface geological conditions of Agung volcano. We found two types of seismicity during the recording period that represent the VT events relating to fracture network reactivation due to stress changes (during the seismic crisis) and magma intrusion (after the seismic crisis). The characteristics of each event type are discussed in terms of Vp/Vs values, phase delay times, seismic cluster shapes, and waveform similarity. We interpret that the upward migrating magma reached a barrier (probably a stiff layer) which prohibited further ascent. Consequently, magma pressurized the zone above the magma chamber and beneath the barrier, reactivated the fracture zone between Agung and Batur volcanoes, and caused the seismic crisis since September 2017. In early November 2017, the barrier was finally intruded, and magma and seismicity propagated toward the Agung summit. This reconstruction provides a better depth constraint as to the previous conceptual models and explains the long delay (∼10 weeks) between the onset of the seismic crisis and the eruption. The distinction between the fracture reactivation and magma intrusion VT events observed in this study is significant for eruption forecasting and understanding the subsurface structure of the magmatic system. Based on the results obtained in this study, we emphasize the importance of prompt analysis (location and basic seismic characteristics) of the seismic crisis preceding the Agung eruption.
High-Wind Drag Coefficient Based on the Tropical Cyclone Simulated With the WRF-LES Framework
Authors: Jiang Wenrui , Wu Liguang , Liu Qingyuan
Published: May 2021

The numerical simulation of tropical cyclones has been increasingly conducted using the advanced Weather Research and Forecast (WRF) model with the large-eddy simulation (LES) technique. Given the importance of the boundary wind profile for the vertical exchange of horizontal momentum between the atmosphere and the ocean, the drag coefficient was evaluated in the numerical simulation with the WRF-LES framework at the finest horizontal grid spacing of 37 m. In the absence of the TC–ocean interaction, the drag coefficient derived from the simulated wind profile does not show the leveling off or decrease in the strong wind conditions. The drag coefficient increases with the increasing near-surface wind speed and agrees well with the extrapolation of the Large and Pond formula in the strong wind conditions. It is suggested that the boundary wind structure simulated with the LES technique may be unrealistic when the TC–ocean interaction is not fully considered.
Effects of Aerobic Exercise Training on Systemic Biomarkers and Cognition in Late Middle-Aged Adults at Risk for Alzheimer’s Disease
Authors: Gaitán Julian M. , Moon Hyo Youl , Stremlau Matthew , Dubal Dena B. , Cook Dane B. , Okonkwo Ozioma C. , van Praag Henriette
Published: May 2021

Increasing evidence indicates that physical activity and exercise training may delay or prevent the onset of Alzheimer’s disease (AD). However, systemic biomarkers that can measure exercise effects on brain function and that link to relevant metabolic responses are lacking. To begin to address this issue, we utilized blood samples of 23 asymptomatic late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50% female) who underwent 26 weeks of supervised treadmill training. Systemic biomarkers implicated in learning and memory, including the myokine Cathepsin B (CTSB), brain-derived neurotrophic factor (BDNF), and klotho, as well as metabolomics were evaluated. Here we show that aerobic exercise training increases plasma CTSB and that changes in CTSB, but not BDNF or klotho, correlate with cognitive performance. BDNF levels decreased with exercise training. Klotho levels were unchanged by training, but closely associated with change in VO2peak. Metabolomic analysis revealed increased levels of polyunsaturated free fatty acids (PUFAs), reductions in ceramides, sphingo- and phospholipids, as well as changes in gut microbiome metabolites and redox homeostasis, with exercise. Multiple metabolites (~30%) correlated with changes in BDNF, but not CSTB or klotho. The positive association between CTSB and cognition, and the modulation of lipid metabolites implicated in dementia, support the beneficial effects of exercise training on brain function. Overall, our analyses indicate metabolic regulation of exercise-induced plasma BDNF changes and provide evidence that CTSB is a marker of cognitive changes in late middle-aged adults at risk for dementia.
Evaluating the Impact of Urban Blue Space Accessibility on Housing Price: A Spatial Quantile Regression Approach Applied in Changsha, China
Authors: Tuofu Huang , Qingyun He , Dongxiao Yang , Xiao Ouyang
Published: May 2021

Urban nature spaces are increasingly recognized as essential urban features providing crucial amenities to the residents’ health and well-being. While many studies have been conducted focusing on the influence of green spaces on house prices, very few have explored the impact of urban blue spaces. In this study, we analyzed the proximity effects of different types and sizes of urban blue spaces on property value in Changsha metropolis, China, and examined the spatial quantile effect across different housing prices. A two-stage instrumental method (2SLS) hedonic model was employed to evaluate the impact of different types of urban blue space: river (mainstream and tributary), wetland park, and lakes (large, medium, and small). Spatial quantile regression (SQR) was then used to measure the spatial effect of accessibility on various house price ranges. The 2SLS results show that, except for small-sized lakes, proximity to blue spaces significantly increases property value. Analysis of the SQR model reveals that proximity to major blue spaces increases the marginal willingness-to-pay among homebuyers of high-priced properties, while ordinary blue spaces are more attractive to buyers of low- and medium-priced houses. This may be broadly related to the level of education, utility, and sensitivity to ecosystem services across income groups. Based on these findings, we recommend that urban planners adopt different strategies to promote space utilization efficiency. This is one of the few studies that analyze the capitalization of blue space accessibility in house prices across different quantiles. By categorizing blue spaces and employing the SQR model, this study found the effect of blue spaces on housing prices to be heterogeneous, providing new perspectives to the existing literature.
Bayesian Predictions of Bark Beetle Attack and Mortality of Three Conifer Species During Epidemic and Endemic Population Stages
Authors: Bretfeld Mario , Speckman Heather N. , Beverly Daniel P. , Ewers Brent E.
Published: May 2021

Bark beetles naturally inhabit forests and can cause large-scale tree mortality when they reach epidemic population numbers. A recent epidemic (1990s–2010s), primarily driven by mountain pine beetles (Dendroctonus ponderosae), was a leading mortality agent in western United States forests. Predictive models of beetle populations and their impact on forests largely depend on host related parameters, such as stand age, basal area, and density. We hypothesized that bark beetle attack patterns are also dependent on inferred beetle population densities: large epidemic populations of beetles will preferentially attack large-diameter trees, and successfully kill them with overwhelming numbers. Conversely, small endemic beetle populations will opportunistically attack stressed and small trees. We tested this hypothesis using 12 years of repeated field observations of three dominant forest species (lodgepole pine Pinus contorta, Engelmann spruce Picea engelmannii, and subalpine fir Abies lasiocarpa) in subalpine forests of southeastern Wyoming paired with a Bayesian modeling approach. The models provide probabilistic predictions of beetle attack patterns that are free of assumptions required by frequentist models that are often violated in these data sets. Furthermore, we assessed seedling/sapling regeneration in response to overstory mortality and hypothesized that higher seedling/sapling establishment occurs in areas with highest overstory mortality because resources are freed from competing trees. Our results indicate that large-diameter trees were more likely to be attacked and killed by bark beetles than small-diameter trees during epidemic years for all species, but there was no shift toward preferentially attacking small-diameter trees in post-epidemic years. However, probabilities of bark beetle attack and mortality increased for small diameter lodgepole pine and Engelmann spruce trees in post-epidemic years compared to epidemic years. We also show an increase in overall understory growth (graminoids, forbs, and shrubs) and seedling/sapling establishment in response to beetle-caused overstory mortality, especially in lodgepole pine dominated stands. Our observations provide evidence of the trajectories of attack and mortality as well as early forest regrowth of three common tree species during the transition from epidemic to post-epidemic stages of bark beetle populations in the field.
PLAU Promotes Cell Proliferation and Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma
Authors: Chen Guangjin , Sun Jiwei , Xie Mengru , Yu Shaoling , Tang Qingming , Chen Lili
Published: May 2021

Plasminogen activator, urokinase (uPA) is a secreted serine protease whose Dysregulation is often accompanied by various cancers. However, the biological functions and potential mechanisms of PLAU in head and neck squamous cell carcinoma (HNSCC) remain undetermined. Here, the expression, prognosis, function, and coexpression genetic networks of PLAU in HNSCC were investigated by a series of public bioinformatics tools. A Higher PLAU level predicted a poorer clinical outcome. Meanwhile, functional network analysis implied that PLAU and associated genes mainly regulated cell-substrate adhesion, tissue migration, and extracellular matrix binding. The top 4 significantly associated genes are C10orf55, ITGA5, SERPINE1, and TNFRSF12A. Pathway enrichment analysis indicated that PLAU might activate the epithelial-to-mesenchymal transition (EMT) process, which could explain the poor prognosis in HNSCC. Besides, genes associated with PLAU were also enriched in EMT pathways. We further validated the bioinformatics analysis results by in vivo and in vitro experiments. Then, we found that much more PLAU was detected in HNSCC tissues, and the silencing of PLAU inhibit the proliferation, migration, and EMT process of CAL27 cell lines. Notably, the downregulation of PLAU decreased the expression of TNFRSF12A. Moreover, knockdown TNFRSF12A also inhibits cell proliferation and migration. In vivo experiment results indicated that PLAU inhibition could suppress tumor growth. Collectively, PLAU is necessary for tumor progression and can be a diagnostic and prognostic biomarker in HNSCC.
Comparative Analysis of Multiple Neurodegenerative Diseases Based on Advanced Epigenetic Aging Brain
Authors: Shi Feitong , He Yudan , Chen Yao , Yin Xinman , Sha Xianzheng , Wang Yin
Published: May 2021

Background: Neurodegenerative Diseases (NDs) are age-dependent and include Alzheimer’s disease (AD), Parkinson’s disease (PD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), and so on. There have been numerous studies showing that accelerated aging is closely related (even the driver of) ND, thus promoting imbalances in cellular homeostasis. However, the mechanisms of how different ND types are related/triggered by advanced aging are still unclear. Therefore, there is an urgent need to explore the potential markers/mechanisms of different ND types based on aging acceleration at a system level.

Methods: AD, PD, PSP, FTD, and aging markers were identified by supervised machine learning methods. The aging acceleration differential networks were constructed based on the aging score. Both the enrichment analysis and sensitivity analysis were carried out to investigate both common and specific mechanisms among different ND types in the context of aging acceleration.

Results: The extracellular fluid, cellular metabolisms, and inflammatory response were identified as the common driving factors of cellular homeostasis imbalances during the accelerated aging process. In addition, Ca ion imbalance, abnormal protein depositions, DNA damage, and cytoplasmic DNA in macrophages were also revealed to be special mechanisms that further promote AD, PD, PSP, and FTD, respectively.

Conclusion: The accelerated epigenetic aging mechanisms of different ND types were integrated and compared through our computational pipeline.
Complement-Opsonized HIV Modulates Pathways Involved in Infection of Cervical Mucosal Tissues: A Transcriptomic and Proteomic Study
Authors: Svanberg Cecilia , Ellegård Rada , Crisci Elisa , Khalid Mohammad , Borendal Wodlin Ninnie , Svenvik Maria , Nyström Sofia , Birse Kenzie , Burgener Adam , Shankar Esaki M. , Larsson Marie
Published: May 2021

Genital mucosal transmission is the most common route of HIV spread. The initial responses triggered at the site of viral entry are reportedly affected by host factors, especially complement components present at the site, and this will have profound consequences on the outcome and pathogenesis of HIV infection. We studied the initial events associated with host-pathogen interactions by exposing cervical biopsies to free or complement-opsonized HIV. Opsonization resulted in higher rates of HIV acquisition/infection in mucosal tissues and emigrating dendritic cells. Transcriptomic and proteomic data showed a significantly more pathways and higher expression of genes and proteins associated with viral replication and pathways involved in different aspects of viral infection including interferon signaling, cytokine profile and dendritic cell maturation for the opsonized HIV. Moreover, the proteomics data indicate a general suppression by the HIV exposure. This clearly suggests that HIV opsonization alters the initial signaling pathways in the cervical mucosa in a manner that promotes viral establishment and infection. Our findings provide a foundation for further studies of the role these early HIV induced events play in HIV pathogenesis.
A Comprehensive Evaluation of the Relationship Between Different IgG and IgA Anti-Modified Protein Autoantibodies in Rheumatoid Arthritis
Authors: Grönwall Caroline , Liljefors Lisa , Bang Holger , Hensvold Aase H. , Hansson Monika , Mathsson-Alm Linda , Israelsson Lena , Joshua Vijay , Svärd Anna , Stålesen Ragnhild , Titcombe Philip J. , Steen Johanna , Piccoli Luca , Sherina Natalia , Clavel Cyril , Svenungsson Elisabet , Gunnarsson Iva , Saevarsdottir Saedis , Kastbom Alf , Serre Guy , Alfredsson Lars , Malmström Vivianne , Rönnelid Johan , Catrina Anca I. , Lundberg Karin , Klareskog Lars
Published: May 2021

Seropositive rheumatoid arthritis (RA) is characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) with different fine-specificities. Yet, other serum anti-modified protein autoantibodies (AMPA), e.g. anti-carbamylated (Carb), -acetylated (KAc), and malondialdehyde acetaldehyde (MAA) modified protein antibodies, have been described. In this comprehensive study, we analyze 30 different IgG and IgA AMPA reactivities to Cit, Carb, KAc, and MAA antigens detected by ELISA and autoantigen arrays in N=1985 newly diagnosed RA patients. Association with patient characteristics such as smoking and disease activity were explored. Carb and KAc reactivities by different assays were primarily seen in patients also positive for anti-citrulline reactivity. Modified vimentin (mod-Vim) peptides were used for direct comparison of different AMPA reactivities, revealing that IgA AMPA recognizing mod-Vim was mainly detected in subsets of patients with high IgG anti-Cit-Vim levels and a history of smoking. IgG reactivity to acetylation was mainly detected in a subset of patients with Cit and Carb reactivity. Anti-acetylated histone reactivity was RA-specific and associated with high anti-CCP2 IgG levels, multiple ACPA fine-specificities, and smoking status. This reactivity was also found to be present in CCP2+ RA-risk individuals without arthritis. Our data further demonstrate that IgG autoreactivity to MAA was increased in RA compared to controls with highest levels in CCP2+ RA, but was not RA-specific, and showed low correlation with other AMPA. Anti-MAA was instead associated with disease activity and was not significantly increased in CCP2+ individuals at risk of RA. Notably, RA patients could be subdivided into four different subsets based on their AMPA IgG and IgA reactivity profiles. Our serology results were complemented by screening of monoclonal antibodies derived from single B cells from RA patients for the same antigens as the RA cohort. Certain CCP2+ clones had Carb or Carb+KAc+ multireactivity, while such reactivities were not found in CCP2- clones. We conclude that autoantibodies exhibiting different patterns of ACPA fine-specificities as well as Carb and KAc reactivity are present in RA and may be derived from multireactive B-cell clones. Carb and KAc could be considered reactivities within the “Cit-umbrella” similar to ACPA fine-specificities, while MAA reactivity is distinctly different.
Dickkopf-1: A Promising Target for Cancer Immunotherapy
Authors: Chu Hang Yin , Chen Zihao , Wang Luyao , Zhang Zong-Kang , Tan Xinhuan , Liu Shuangshuang , Zhang Bao-Ting , Lu Aiping , Yu Yuanyuan , Zhang Ge
Published: May 2021

Clinical studies in a range of cancers have detected elevated levels of the Wnt antagonist Dickkopf-1 (DKK1) in the serum or tumors of patients, and this was frequently associated with a poor prognosis. Our analysis of DKK1 gene profile using data from TCGA also proves the high expression of DKK1 in 14 types of cancers. Numerous preclinical studies have demonstrated the cancer-promoting effects of DKK1 in both in vitro cell models and in vivo animal models. Furthermore, DKK1 showed the ability to modulate immune cell activities as well as the immunosuppressive cancer microenvironment. Expression level of DKK1 is positively correlated with infiltrating levels of myeloid-derived suppressor cells (MDSCs) in 20 types of cancers, while negatively associated with CD8+ T cells in 4 of these 20 cancer types. Emerging experimental evidence indicates that DKK1 has been involved in T cell differentiation and induction of cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms of DKK1 affecting cancers and immune cells have received great attention. This review introduces the rapidly growing body of literature revealing the cancer-promoting and immune regulatory activities of DKK1. In addition, this review also predicts that by understanding the interaction between different domains of DKK1 through computational modeling and functional studies, the underlying functional mechanism of DKK1 could be further elucidated, thus facilitating the development of anti-DKK1 drugs with more promising efficacy in cancer immunotherapy.
The Long Pentraxin PTX3 Controls Klebsiella Pneumoniae Severe Infection
Authors: Asgari Fatemeh , Supino Domenico , Parente Raffaella , Polentarutti Nadia , Stravalaci Matteo , Porte Remi , Pasqualini Fabio , Barbagallo Marialuisa , Perucchini Chiara , Recordati Camilla , Magrini Elena , Mariancini Andrea , Riva Federica , Giordano Alessia , Davoudian Sadaf , Roger Thierry , Veer Cornelis van’t , Jaillon Sebastien , Mantovani Alberto , Doni Andrea , Garlanda Cecilia
Published: May 2021

Klebsiella pneumoniae is a common pathogen in human sepsis. The emergence of multidrug-resistant K. pneumoniae strains represents a major clinical challenge in nosocomial and community acquired infections. The long pentraxin PTX3, a key component of humoral innate immunity, is involved in resistance to selected pathogens by promoting opsonophagocytosis. We investigated the relevance of PTX3 in innate immunity against K. pneumoniae infections using Ptx3-/- mice and mouse models of severe K. pneumoniae infections. Local and systemic PTX3 expression was induced following K. pneumoniae pulmonary infection, in association with the up-regulation of TNF-α and IL-1β. PTX3 deficiency in mice was associated with higher bacterial burden and mortality, release of pro-inflammatory cytokines as well as IL-10 in the lung and systemically. The analysis of the mechanisms responsible of PTX3-dependent control of K. pneumoniae infection revealed that PTX3 did not interact with K. pneumoniae, or promote opsonophagocytosis. The comparison of susceptibility of wild-type, Ptx3-/-, C3-/- and Ptx3-/-/C3-/- mice to the infection showed that PTX3 acted in a complement-independent manner. Lung histopathological analysis showed more severe lesions in Ptx3-/- mice with fibrinosuppurative, necrotizing and haemorrhagic bronchopneumonia, associated with increased fibrin deposition in the lung and circulating fibrinogen consumption. These findings indicate that PTX3 contributes to the control of K. pneumoniae infection by modulating inflammatory responses and tissue damage. Thus, this study emphasizes the relevance of the role of PTX3 as regulator of inflammation and orchestrator of tissue repair in innate responses to infections.
Antidepressants on Multiple Sclerosis: A Review of In Vitro and In Vivo Models
Authors: Stamoula Eleni , Siafis Spyridon , Dardalas Ioannis , Ainatzoglou Alexandra , Matsas Alkis , Athanasiadis Theodoros , Sardeli Chrysanthi , Stamoulas Konstantinos , Papazisis Georgios
Published: May 2021

Background

Increased prevalence of depression has been observed among patients with multiple sclerosis (MS) and correlated with the elevated levels of proinflammatory cytokines and the overall deregulation of monoaminergic neurotransmitters that these patients exhibit. Antidepressants have proved effective not only in treating depression comorbid to MS, but also in alleviating numerous MS symptoms and even minimizing stress-related relapses. Therefore, these agents could prospectively prove beneficial as a complementary MS therapy.

Objective

This review aims at illustrating the underlying mechanisms involved in the beneficial clinical effects of antidepressants observed in MS patients.

Methods

Through a literature search we screened and comparatively assessed papers on the effects of antidepressant use both in vitro and in vivo MS models, taking into account a number of inclusion and exclusion criteria.

Results

In vitro studies indicated that antidepressants promote neural and glial cell viability and differentiation, reduce proinflammatory cytokines and exert neuroprotective activity by eliminating axonal loss. In vivo studies confirmed that antidepressants delayed disease onset and alleviated symptoms in Experimental Autoimmune Encephalomyelitis (EAE), the most prevalent animal model of MS. Further, antidepressant agents suppressed inflammation and restrained demyelination by decreasing immune cell infiltration of the CNS.

Conclusion

Antidepressants were efficient in tackling numerous aspects of disease pathophysiology both in vitro and in vivo models. Given that several antidepressants have already proved effective in clinical trials on MS patients, the inclusion of such agents in the therapeutic arsenal of MS should be seriously considered, following an individualized approach to minimize the adverse events of antidepressants in MS patients.
CD47 Deficiency Ameliorates Ocular Autoimmune Inflammation
Authors: Okunuki Yoko , Tabor Steven J. , Lee May Y. , Connor Kip M.
Published: May 2021

Autoimmune uveitis is a sight-threatening ocular inflammatory condition in which the retina and uveal tissues become a target of autoreactive immune cells. The CD47 is a ubiquitously expressed transmembrane protein which plays multiple roles in fundamental cellular functions including phagocytosis, proliferation, and adhesion. Signal regulatory protein alpha (SIRPα), one of the CD47 ligands, is predominantly expressed in myeloid lineage cells such as dendritic cells (DCs) or macrophages, and CD47-SIRPα signaling pathway is implicated in the development of autoimmune diseases. Our current study demonstrates how CD47 depletion is effective in the prevention of experimental autoimmune uveitis (EAU), an animal model of human autoimmune uveitis, in animals deficient of CD47 (CD47-/-). Systemic suppression of SIRPα+DCs in animals deficient in CD47 resulted in the inability of autoreactive CD4+T cells to develop, which is crucial to induction of EAU. Of interest, retinal microglia, the resident immune cell of the retina, express SIRPα, however these cells were not operative in EAU suppression in response to CD47 depletion. These results identify CD47 as a significant regulator in the development of SIRPα+DCs that is vital to disease induction in EAU.
Broad T Cell Targeting of Structural Proteins After SARS-CoV-2 Infection: High Throughput Assessment of T Cell Reactivity Using an Automated Interferon Gamma Release Assay
Authors: Brand Isabel , Gilberg Leonard , Bruger Jan , Garí Mercè , Wieser Andreas , Eser Tabea M. , Frese Jonathan , Ahmed Mohamed I. M. , Rubio-Acero Raquel , Guggenbuehl Noller Jessica M. , Castelletti Noemi , Diekmannshemke Jana , Thiesbrummel Sophie , Huynh Duc , Winter Simon , Kroidl Inge , Fuchs Christiane , Hoelscher Michael , Roider Julia , Kobold Sebastian , Pritsch Michael , Geldmacher Christof
Published: May 2021

Background

Adaptive immune responses to structural proteins of the virion play a crucial role in protection against coronavirus disease 2019 (COVID-19). We therefore studied T cell responses against multiple SARS-CoV-2 structural proteins in a large cohort using a simple, fast, and high-throughput approach.

Methods

An automated interferon gamma release assay (IGRA) for the Nucleocapsid (NC)-, Membrane (M)-, Spike-C-terminus (SCT)-, and N-terminus-protein (SNT)-specific T cell responses was performed using fresh whole blood from study subjects with convalescent, confirmed COVID-19 (n = 177, more than 200 days post infection), exposed household members (n = 145), and unexposed controls (n = 85). SARS-CoV-2-specific antibodies were assessed using Elecsys® Anti-SARS-CoV-2 (Ro-N-Ig) and Anti-SARS-CoV-2-ELISA (IgG) (EI-S1-IgG).

Results

156 of 177 (88%) previously PCR confirmed cases were still positive by Ro-N-Ig more than 200 days after infection. In T cells, most frequently the M-protein was targeted by 88% seropositive, PCR confirmed cases, followed by SCT (85%), NC (82%), and SNT (73%), whereas each of these antigens was recognized by less than 14% of non-exposed control subjects. Broad targeting of these structural virion proteins was characteristic of convalescent SARS-CoV-2 infection; 68% of all seropositive individuals targeted all four tested antigens. Indeed, anti-NC antibody titer correlated loosely, but significantly with the magnitude and breadth of the SARS-CoV-2-specific T cell response. Age, sex, and body mass index were comparable between the different groups.

Conclusion

SARS-CoV-2 seropositivity correlates with broad T cell reactivity of the structural virus proteins at 200 days after infection and beyond. The SARS-CoV-2-IGRA can facilitate large scale determination of SARS-CoV-2-specific T cell responses with high accuracy against multiple targets.