bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Si and Al contents and isothermal treatment condition on the microstructure and tensile properties in ultra-high strength Fe-0.2C-2.0Mn martensite-bainite complex phase steels
Authors: Lee Eung Hyuk , Yu Chang Jae , Lee Hong-Bum , Kim Ji-Hoon , Suh Dong-Woo
Published: August 2021

This study investigated the influence of partial replacement of Si by Al on the microstructure and tensile properties of ultra-high strength steels with martensite-bainite complex microstructure produced by austenitization and subsequent isothermal heat treatment around Ms temperature. When the isothermal heat treatment was done below the Ms temperature, the fraction of martensite increased with the lower isothermal temperature, but the fractions of constituent phases in the final microstructure were not significantly affected by the partial replacement of Si by Al. Nevertheless, the increase in Al content in the complex phase steel accelerated the bainite transformation, which is thought to be associated with the increase of the free energy difference between FCC and BCC. The enhancement of the bainite transformation not only effectively suppressed the martensite formation upon final cooling when the isothermal temperature was above the Ms temperature but also helped refine the final microstructure when subjected to isothermal heat treatment below the Ms temperature. The yield strengths of the investigated complex phase steels were little influenced by the partial replacement of Si with Al, as long as the fractions of the constituent phases were comparable. This possibly originates with the solid solution hardening and the microstructure refinement with Al addition.
Development of PosMAC® Steel and Its Application Properties
Authors: Sohn Il-Ryoung , Kim Tae-Chul , Ju Gwang-Il , Kim Myung-Soo , Kim Jong-Sang
Published: August 2021

PosMAC® is a hot dipping Zn-Mg-Al coated steel sheet developed by POSCO. PosMAC®3.0 shows excellent anti-corrosion performance and is suitable for construction and solar energy systems in severe corrosive environments. PosMAC®1.5 has a superior surface quality and is preferred for automotive and home appliances. The advanced anti-corrosion properties of PosMAC® comes from a dense corroded layer which forms on coated surfaces, compared with traditional Zn coatings such as GI, GA and EG. PosMAC® steels show superior corrosion protection compared to GI coatings in cyclic corrosion tests, despite an approximate 30% reduction in coating weight. The PosMAC® has excellent application properties for the arc welding of automotive chassis. It has a heat resistance that is more robust than the GI coating, and maintains excellent corrosion protection near the welds of the chassis. Zn-Mg-Al coatings, whose chemical compositions are similar to PosMAC® coatings, have very low surface friction properties compared to the GI coating. The friction coefficient of PosMAC® is stabilized to 0.09~0.11. In contrast, the GI coating showed higher friction coefficients of 0.2~0.3 in the repeated friction test. PosMAC® would be appropriate for complex forming parts with less galling, given these low friction resistance properties. It is expected that the industrial demand for PosMAC® steel will increase in the near future, thanks to its Zn saving and high anti-corrosion performance.
Fabrication of Semi-transparent W film Heaters via Phase Transformation
Authors: Choi Jiyun , Choi Dooho
Published: August 2021

In this study, we prepared highly thermostable semi-transparent heaters composed of W layers with thicknesses of 1-20 nm, on which a 30 nm-thick ZnO layer was deposited to serve as an anti-oxidation barrier. The optical transmittance and sheet resistance of the heaters could be greatly modulated by varying the W layer thickness. For layer thicknesses up to 10 nm, the initial Joule heating above 100 oC significantly reduced the sheet resistance, by 300% for a 6 nm-thick W layer at a fixed voltage for a duration of 400 s. During the test period, heater current and heating capability continuously increased. In subsequent heater operations, the heaters exhibited highly reproducible heating capability. In contrast, for films thicker than 10 nm, the Joule heating process resulted in only a marginal reduction in sheet resistance, i.e., by 4% for a 20 nm-thick W layer. In order to investigate the sharp dependence of heater characteristics on thickness, we performed x-ray diffraction analyses, which revealed that the films thinner than 10 nm were composed of both the equilibrium low-resistivity α-phase and metastable high-resistivity β-phase, and films thicker than 10 nm contained mostly α-phase. The Joule heating process for the thinner films was found to transform the β-phase into α-phase at temperatures above 100 oC, which resulted in significant improvement in the heating capability of the 6 nm-thick W layer. For films thicker than 10 nm, the W layers contained mostly α-phase and no such transformation-induced effects were observed. Finally, W heaters composed of α-phase exhibited highly thermostable and reproducible heater properties, which make the heaters suitable for applications with semi-transparent heaters.
The Leibnizian Lineage of Deleuze's Theory of theSpatium
Authors: Vermeiren Florian
Published: August 2021

This paper examines the Leibnizian influence in Deleuze's theory of the spatium. Leibniz's critique of Cartesian extension and Newtonian space leads him to a conception of space in terms of internal determination and internal difference. Space is thus understood as a structure of individual relations internal to substances. Making some Nietzschean corrections to Leibniz, Deleuze understands the spatium in terms of individuating differences instead of individual relations. Leibnizian space is thus transformed into a genetic space producing both extension (quantity) and quality.
Black Seedcoat Pigmentation Is a Marker for Enhanced Nodulation and N2 Fixation in Bambara Groundnut (Vigna Subterranea L. Verdc.) Landraces
Authors: Puozaa Doris K. , Jaiswal Sanjay K. , Dakora Felix D.
Published: August 2021

Field studies on the effect of differing seedcoat colour on plant growth and symbiotic performance of three Bambara groundnut landraces using the 15N natural abundance technique and ureide analysis in the xylem stream and petiole extracts revealed a consistent pattern in nodule function between ureide levels and shoot δ15N values, as well as between ureide levels and percent N derived from fixation at Gbalahi, Kpalisogu, and Manga. At those three sites, where shoot δ15N was low and percent N derived from fixation high, ureide concentrations in the xylem sap and petiole extracts were also high, indicating that the two techniques were comparatively quite robust in estimating N2 fixation at a higher precision in the test Bambara groundnut landraces. A comparison of the effect of differing seedcoat pigmentation on the concentration of phenolics released by imbibed seeds showed that the Black landrace contained higher levels of flavonoids and anthocyanins, followed by the Red, and lowest in the Cream landrace. The Black landrace also recorded much higher nodule number and nodule fresh weight per plant, greater shoot biomass, lower shoot δ15N values, greater N derived from fixation, higher symbiotic N contribution, and increased water-use efficiency across all the five study sites, followed by the Red landrace, which produced the highest grain yield. Black seedcoat pigmentation in Bambara groundnut is therefore a marker for increased nodulation, N2 fixation, and plant growth that can be tapped in breeding programs for developing high N2-fixing, water-use efficient grain legumes for use by farmers in Africa.
The Role and Regulatory Mechanism of Transcription Factor EB in Health and Diseases
Authors: Zhu Sheng-yu , Yao Ren-qi , Li Yu-xuan , Zhao Peng-yue , Ren Chao , Du Xiao-hui , Yao Yong-ming
Published: August 2021

Transcription factor EB (TFEB) is a member of the microphthalmia-associated transcription factor/transcription factor E (MiTF/TFE) family and critically involved in the maintenance of structural integrity and functional balance of multiple cells. In this review, we described the effects of post-transcriptional modifications, including phosphorylation, acetylation, SUMOylation, and ubiquitination, on the subcellular localization and activation of TFEB. The activated TFEB enters into the nucleus and induces the expressions of targeted genes. We then presented the role of TFEB in the biosynthesis of multiple organelles, completion of lysosome-autophagy pathway, metabolism regulation, immune, and inflammatory responses. This review compiles existing knowledge in the understanding of TFEB regulation and function, covering its essential role in response to cellular stress. We further elaborated the involvement of TFEB dysregulation in the pathophysiological process of various diseases, such as the catabolic hyperactivity in tumors, the accumulation of abnormal aggregates in neurodegenerative diseases, and the aberrant host responses in inflammatory diseases. In this review, multiple drugs have also been introduced, which enable regulating the translocation and activation of TFEB, showing beneficial effects in mitigating various disease models. Therefore, TFEB might serve as a potential therapeutic target for human diseases. The limitation of this review is that the mechanism of TFEB-related human diseases mainly focuses on its association with lysosome and autophagy, which needs deep description of other mechanism in diseases progression after getting more advanced information.
Expanding the Chondroitin Sulfate Glycoproteome — But How Far?
Authors: Noborn Fredrik , Nikpour Mahnaz , Persson Andrea , Nilsson Jonas , Larson Göran
Published: August 2021

Chondroitin sulfate proteoglycans (CSPGs) are found at cell surfaces and in connective tissues, where they interact with a multitude of proteins involved in various pathophysiological processes. From a methodological perspective, the identification of CSPGs is challenging, as the identification requires the combined sequencing of specific core proteins, together with the characterization of the CS polysaccharide modification(s). According to the current notion of CSPGs, they are often considered in relation to a functional role in which a given proteoglycan regulates a specific function in cellular physiology. Recent advances in glycoproteomic methods have, however, enabled the identification of numerous novel chondroitin sulfate core proteins, and their glycosaminoglycan attachment sites, in humans and in various animal models. In addition, these methods have revealed unexpected structural complexity even in the linkage regions. These findings indicate that the number and structural complexity of CSPGs are much greater than previously perceived. In light of these findings, the prospect of finding additional CSPGs, using improved methods for structural and functional characterizations, and studying novel sample matrices in humans and in animal models is discussed. Further, as many of the novel CSPGs are found in low abundance and with not yet assigned functions, these findings may challenge the traditional notion of defining proteoglycans. Therefore, the concept of proteoglycans is considered, discussing whether “a proteoglycan” should be defined mainly on the basis of an assigned function or on the structural evidence of its existence.
Above the Matrix: Functional Roles for Apically Localized Integrins
Authors: Peterson Raven J. , Koval Michael
Published: August 2021

Integrins are transmembrane proteins that are most typically thought of as integrating adhesion to the extracellular matrix with intracellular signaling and cell regulation. Traditionally, integrins are found at basolateral and lateral cell surfaces where they facilitate binding to the ECM and intercellular adhesion through cytosolic binding partners that regulate organization of actin microfilaments. However, evidence is accumulating that integrins also are apically localized, either endogenously or due to an exogenous stimulus. Apically localized integrins have been shown to regulate several processes by interacting with proteins such as connexins, tight junction proteins, and polarity complex proteins. Integrins can also act as receptors to mediate endocytosis. Here we review these newly appreciated roles for integrins localized to the apical cell surface.
A Two-Gene-Based Diagnostic Signature for Ruptured Intracranial Aneurysms
Authors: Li Yuwang , Qin Jie
Published: August 2021

Background: Ruptured intracranial aneurysm (IA) is a disease with high mortality. Despite the great progress in treating ruptured IA, methods for risk assessment of ruptured IA remain limited.

Methods: In this study, we aim to develop a robust diagnostic model for ruptured IA. Gene expression profiles in blood samples of 18 healthy persons and 43 ruptured IA patients were obtained from the Gene Expression Omnibus (GEO). Differential expression analysis was performed using limma Bioconductor package followed by functional enrichment analysis via clusterProfiler Bioconductor package. Immune cell compositions in ruptured IA and healthy samples were assessed through the CIBERSORT tool. Protein–protein interaction (PPI) was predicted based on the STRING database. Logistic regression model was used for the construction of predictive model for distinguishing ruptured IA and healthy samples. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to validate the gene expression between the ruptured IA and healthy samples.

Results: A total of 58 differentially expressed genes (DEGs) were obtained for ruptured IA patients compared with healthy controls. Functional enrichment analysis showed that the DEGs were enriched in biological processes related to neutrophil activation, neutrophil degranulation, and cytokine–cytokine receptor interaction. Notably, immune analysis results proved that the rupture of IA might be related to immune cell distribution. We further identified 24 key genes as hub genes using the PPI networks. The logistic regression model trained based on the 24 key genes ultimately retained two genes, i.e., IL2RB and CCR7, which had great potential for risk assessment for rupture of IA. The RT-qPCR further validated that compared with the healthy samples, the expression levels of IL2RB and CCR7 were decreased in ruptured IA samples.

Conclusions: This study might be helpful for cohorts who have a high risk of ruptured IA for early diagnosis and prevention of the disease.
The Central Role of Left Atrium in Heart Failure
Authors: Carpenito Myriam , Fanti Diego , Mega Simona , Benfari Giovanni , Bono Maria Caterina , Rossi Andrea , Ribichini Flavio Luciano , Grigioni Francesco
Published: August 2021

In past cardiovascular medicine, the attention to the left ventricle-identified as the only indicator and determinant of healthy or unhealthy cardiac conditions- has systematically hidden the role of the left atrium (LA). The recent advances in cardiovascular imaging have provided a better understanding of LA anatomy, physiology, and pathology, making us realize that this functional structure is far from being an innocent spectator. We now know that the LA's mechanical and neuro-hormonal properties play a relevant part in several cardiovascular diseases, including atrial fibrillation, ischemic heart disease, valvular heart disease, and heart failure. The present review aims to describe the role of LA in the specific setting of heart failure. We provide currently available information on LA structure and function and summarize its role as a determinant of symptoms, prognosis, and potential therapeutic target in heart failure patients.
Case Report: BAF-Opathies/SSRIDDs Due to a de novo ACTL6A Variant, Previously Considered to Be Heart-Hand Syndrome
Authors: Yuan Zhuang-Zhuang , Xie Xiao-Hui , Gu Heng , Zhang Wei-Zhi , Hu Yi-Qiao , Yang Yi-Feng , Tan Zhi-Ping
Published: August 2021

Purpose: This study aims to identify genetic lesions in patients with congenital heart disease (CHD) with or without other phenotypes. In this study, over 400 patients were recruited and several novel variants in known causative genes were identified. A Chinese patient clinically diagnosed with HHS (patent ductus arteriosus, persistent left superior vena cava, and congenital absence of left arm radius) was included in the study cohort.

Methods: Targeted, whole exome, and Sanger sequencing were performed to identify genetic lesions. The effects of the variant on ACTL6A RNA and protein were assessed using bioinformatics analysis.

Results: At the start of the study, no mutations in known and candidate causative genes associated with CHD were identified. Seven years later, we noticed craniofacial deformities and identified a de novo heterozygous deletion variant in ACTL6A (NM_004301, c.478_478delT; p.F160Lfs*9). Intellectual disability and short stature were identified by a follow-up visit 10 years later. This variant leads to frameshift sequences and a premature termination codon and may affect the features of proteins. According to the nonsense-mediated mRNA decay theory, this variant may induce the decay of ACTL6A mRNA in patients.

Conclusion: Our study reported the first ACTL6A variant in a Chinese individual, providing further evidence that ACTL6A is involved in heart and upper limb skeletal and intellectual development, thereby expanding the spectrum of ACTL6A variants. Thus, mutation analysis of the ACTL6A gene should be considered in patients with BAF-opathies or heart-hand syndromes due to potential misdiagnosis. Craniofacial dysmorphisms and intellectual disability are key to distinguishing these two diseases clinically, and attention to developmental delay/intellectual disability and craniofacial deformities will contribute to the diagnosis of BAF-opathies.
Pulmonary Embolism in COVID-19 Patients: Which Diagnostic Algorithm Should We Use?
Authors: Porfidia Angelo , Mosoni Carolina , Talerico Rosa , Porceddu Enrica , Lupascu Andrea , Tondi Paolo , Landi Francesco , Pola Roberto
Published: August 2021

Introduction: Although pulmonary embolism (PE) is a frequent complication of the clinical course of COVID-19, there is a lack of explicit indications regarding the best algorithm for diagnosing PE in these patients. In particular, it is not clear how to identify subjects who should undergo computed tomography pulmonary angiography (CTPA), rather than simply X-ray and/or high resolution computed tomography (HRCT) of the chest.

Methods: We retrospectively analyzed COVID-19 patients who presented to the Emergency Department (ED) of our University hospital with acute respiratory failure, or that developed acute respiratory failure during hospital stay, to determine how many of them had a theoretical indication to undergo CTPA for suspected PE according to current guidelines. Next, we looked for differences between patients who underwent CTPA and those who only underwent X-ray and/or HRCT of the chest. Finally, we determined whether patients with a confirmed diagnosis of PE had specific characteristics that made them different from those with a CTPA negative for PE.

Results: Out of 93 subjects with COVID-19 and acute respiratory failure, 73 (78.4%) had an indication to undergo CTPA according to the revised Geneva and Wells scores and the PERC rule-out criteria, and 54 (58%) according to the YEARS algorithm. However, in contrast with these indications, only 28 patients (30.1%) underwent CTPA. Of note, they were not clinically different from those who underwent X-ray and/or HRCT of the chest. Among the 28 subjects who underwent CTPA, there were 10 cases of PE (35.7%). They were not clinically different from those with CTPA negative for PE.

Conclusions: COVID-19 patients with acute respiratory failure undergo CTPA, X-ray of the chest, or HRCT without an established criterion. Nonetheless, when CTPA is performed, the diagnosis of PE is anything but rare. Validated tools for identifying COVID-19 patients who require CTPA for suspected PE are urgently needed.
Geological Characteristics and Distribution of Granite Geothermal Reservoir in Southeast Coastal Areas in China
Authors: Zheng Herong , Luo Jun , Zhang Ying , Feng Jianyun , Zeng Yan , Wang Mingchuan
Published: August 2021

The southeast coastal areas in China have distributed lots of granite outcrops of different periods. Previous research has shown that granite geothermal reservoirs are also distributed under sedimentary basins in these areas, such as in Zhangzhou basin. Therefore, granites with fractures buried in deep can be used as a potential deep geothermal reservoir in these areas. In order to study geological conditions of the deep granite reservoir and discuss the genesis of the deep granite geothermal system, rock geochemistry and zircon U-Pb chronology from outcrop and parts of the drilling cores of granitic rocks have been analyzed, combined with the anatomy of the deep seismic data and electromagnetic detection data in selected area. Based on the results of geochemistry and zircon U-Pb chronology, most granites in this area are of Yanshanian periods. Based on the seismic data, the thickness of the overlying strata on granite in Huangshadong area of Huizhou City is up to 1.5 km. According to the regional geological survey, multi-stage joints are developed in the granite, and most of hot springs rise from intersection of fracture with different directions to the surface. The heat source in the study area mainly comes from the mantle carried up by the deep NNE-trending faults. There are a large number of thermal springs at the intersection of the surface and the NW-trending fault, and the NW-trending fault provides the drainage conditions for the upwelling of underground thermal springs. There is a huge amount of deep granite geothermal resources in the southeast coastal area. The analysis of deep granite geological conditions and genetic models can provide guidance for the evaluation of deep granite geothermal resources and the further optimization of favorable zones in these areas.
A Potential Canary in the Coal Mine: A Critical Policy Analysis of the Illinois LSAMP During the COVID-19 Pandemic
Authors: Morgan Demetri L. , Callais Victoria E. , Acevedo Maria , Davis Kendrick B.
Published: August 2021

The COVID-19 pandemic has continued to impact every industry and test problem-solving capabilities and innovation across the board; education is no exception. As institutions continue to adapt to the impacts of the current public health crisis, colleges and universities are also navigating federal policy prompted by the pandemic. Literature has shown the positive influence of organizations, such as the Louis Stokes Alliances for Minority Participation (LSAMP), and, we argue that they can take a more active intermediary approach, that of an Organizational Buffer, to best support their students during times of uncertainty. Current research highlights the disconnect between STEM education and policy, as well as how the pandemic is disproportionately impacting communities of color. The pervasiveness of whiteness within educational policy and the negative impacts of unequal distribution of resources on students of color in STEM highlight the need to center race in a theoretical framework and policy. The purpose of this study was to understand the policy and communication responses to the pandemic as they pertained to supporting student success in STEM. Using the Theory of Racialized Organizations, which is a qualitative case study approach that leverages diffractive readings, was implemented to understand whether educational policy and communication responses during this time have or perpetuated inequitable systems. Guided by the research question, in what ways do pandemic policies and communications bolster the success of underrepresented minoritized students (URM) majoring in STEM, our study found four versions of policymaking (i.e., Performative, Picking Winners and Losers, Stay in your Lane, and Time Burden) that emerged and did not support URM STEM students equitably and consistently. Based on these findings, we present implications for institutional responses, LSAMP-alliance support, and future research.
Cost-Effectiveness of Dipeptidylpeptidase-4 Inhibitors Added to Metformin in Patients With Type 2 Diabetes in China
Authors: Lin Wen-Qiang , Cai Zhong-jie , Chen Tingting , Liu Mao-Bai , Li Na , Zheng Bin
Published: August 2021

Purpose

Dipeptidylpeptidase-4 (DPP-4) inhibitors, including linagliptin, alogliptin, saxagliptin, sitagliptin, and vildagliptin, are used for the treatment of type 2 diabetes mellitus (T2DM) patients in China. This study assessed the economic outcomes of different DPP-4 inhibitors in patients with T2DM inadequately controlled with metformin in the Chinese context.

Materials and Methods

In this study, the validated Chinese Outcomes Model for T2DM (COMT) was conducted to project economic outcomes from the perspective of Chinese healthcare service providers. Efficacy and safety, medical expenditure, and utility data were derived from the literature, which were assigned to model variables. The primary outputs of the model included the lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probability sensitivity analysis was conducted to assess the potential uncertainties of parameters.

Results

Of the five competing strategies, alogliptin 25 mg strategy yielded the most significant health outcome, which associated with improvements in discounted QALY of 0.007, 0.014, 0.011, and 0.022 versus linagliptin 5 mg, saxagliptin 5 mg, sitagliptin 100 mg and vildagliptin50 mg, respectively. The sitagliptin 100 mg strategy was the cheapest option. The ICER of alogliptin 25 mg against sitagliptin 100 mg strategy was $6,952 per additional QALY gained, and the rest of the strategies were dominated or extended dominated. The most influential parameters were the cost of DPP-4 inhibitors and their treatment efficacy.

Conclusions

These results suggested that alogliptin was a preferred treatment option compared with other DPP-4 inhibitors for Chinese patients whose T2DM are inadequately controlled on metformin monotherapy.
Knock-Out of DHTKD1 Alters Mitochondrial Respiration and Function, and May Represent a Novel Pathway in Cardiometabolic Disease Risk
Authors: Wang Chuan , Calcutt M. Wade , Ferguson Jane F.
Published: August 2021

Cardiometabolic disease affects the majority of individuals worldwide. The metabolite α-aminoadipic acid (2-AAA) was identified as a biomarker of Type 2 Diabetes (T2D). However, the mechanisms underlying this association remain unknown. DHTKD1, a central gene in the 2-AAA pathway, has been linked to 2-AAA levels and metabolic phenotypes. However, relatively little is known about its function. Here we report that DHTKD1 knock-out (KO) in HAP-1 cells leads to impaired mitochondrial structure and function. Despite impaired mitochondrial respiration and less ATP production, normal cell proliferation rate is maintained, potentially through a series of compensatory mechanisms, including increased mitochondrial content and Akt activation, p38, and ERK signaling. Common variants in DHTKD1 associate with Type 2 Diabetes and cardiometabolic traits in large genome-wide associations studies. These findings highlight the vital role of DHTKD1 in cellular metabolism and establish DHTKD1-mediated mitochondrial dysfunction as a potential novel pathway in cardiometabolic disease.
Comparing Alternative Jet Fuel Dependencies Between Combustors of Different Size and Mixing Approaches
Authors: Boehm Randall C. , Colborn Jennifer G. , Heyne Joshua S.
Published: August 2021

Analyses used to reveal fuel dependencies on lean blow out and ignition at specific operating conditions in specific combustors show inconsistent trends with each other. Such variety is however consistent with the occurrence of transitions between the governing physical phenomena as the ratios between evaporation, mixing, or chemical time scales with their respective residence times also vary with specific operating conditions and combustor geometry. It is demonstrated here that the fuel dependencies on LBO in a large, single-cup, swirl-stabilized, rich-quench-lean combustor varies with operating conditions such that a feature importance match is attained to fuel dependencies observed in a much smaller combustor at one end of the tested range, while a qualitative match to fuel dependencies observed in a lean, premixed, swirler-stabilized combustor of comparable size at the other end of the tested range. The same reference combustor, when tested at cold conditions, is shown to exhibit similar fuel dependencies on ignition performance as the much smaller combustor, when tested at both cold and warm conditions. The practical significance of these findings is that a reference rig, such as the Referee Rig, can capture fuel performance trends of proprietary industry combustors by tailoring the inlet air and fuel temperatures of the tests. It is, therefore, a trustworthy surrogate for screening and evaluating sustainable aviation fuel candidates, reducing the dependency on proprietary industrial combustors for this purpose, thereby increasing transparency within the evaluation process while also expediting the process and reducing cost and fuel volume.
Site-Dependent Relationships Between Fungal Community Composition, Plant Genotypic Diversity and Environmental Drivers in a Salix Biomass System
Authors: Hoeber Stefanie , Baum Christel , Weih Martin , Manzoni Stefano , Fransson Petra
Published: August 2021

Soil fungi are strongly affected by plant species or genotypes since plants modify their surrounding environment, but the effects of plant genotype diversity on fungal diversity and function have not been extensively studied. The interactive responses of fungal community composition to plant genotypic diversity and environmental drivers were investigated in Salix biomass systems, posing questions about: (1) How fungal diversity varies as a function of plant genotype diversity; (2) If plant genotype identity is a strong driver of fungal community composition also in plant mixtures; (3) How the fungal communities change through time (seasonally and interannually)?; and (4) Will the proportion of ECM fungi increase over the rotation? Soil samples were collected over 4 years, starting preplanting from two Salix field trials, including four genotypes with contrasting phenology and functional traits, and genotypes were grown in all possible combinations (four genotypes in Uppsala, Sweden, two in Rostock, Germany). Fungal communities were identified, using Pacific Biosciences sequencing of fungal ITS2 amplicons. We found some site-dependent relationships between fungal community composition and genotype or diversity level, and site accounted for the largest part of the variation in fungal community composition. Rostock had a more homogenous community structure, with significant effects of genotype, diversity level, and the presence of one genotype (“Loden”) on fungal community composition. Soil properties and plant and litter traits contributed to explaining the variation in fungal species composition. The within-season variation in composition was of a similar magnitude to the year-to-year variation. The proportion of ECM fungi increased over time irrespective of plant genotype diversity, and, in Uppsala, the 4-mixture showed a weaker response than other combinations. Species richness was generally higher in Uppsala compared with that in Rostock and increased over time, but did not increase with plant genotype diversity. This significant site-specificity underlines the need for consideration of diverse sites to draw general conclusions of temporal variations and functioning of fungal communities. A significant increase in ECM colonization of soil under the pioneer tree Salix on agricultural soils was evident and points to changed litter decomposition and soil carbon dynamics during Salix growth.
Forward and Reverse Genetics of B Cell Malignancies: From Insertional Mutagenesis to CRISPR-Cas
Authors: Dawes Joanna C. , Uren Anthony G.
Published: August 2021

Cancer genome sequencing has identified dozens of mutations with a putative role in lymphomagenesis and leukemogenesis. Validation of driver mutations responsible for B cell neoplasms is complicated by the volume of mutations worthy of investigation and by the complex ways that multiple mutations arising from different stages of B cell development can cooperate. Forward and reverse genetic strategies in mice can provide complementary validation of human driver genes and in some cases comparative genomics of these models with human tumors has directed the identification of new drivers in human malignancies. We review a collection of forward genetic screens performed using insertional mutagenesis, chemical mutagenesis and exome sequencing and discuss how the high coverage of subclonal mutations in insertional mutagenesis screens can identify cooperating mutations at rates not possible using human tumor genomes. We also compare a set of independently conducted screens from Pax5 mutant mice that converge upon a common set of mutations observed in human acute lymphoblastic leukemia (ALL). We also discuss reverse genetic models and screens that use CRISPR-Cas, ORFs and shRNAs to provide high throughput in vivo proof of oncogenic function, with an emphasis on models using adoptive transfer of ex vivo cultured cells. Finally, we summarize mouse models that offer temporal regulation of candidate genes in an in vivo setting to demonstrate the potential of their encoded proteins as therapeutic targets.
Roles of Macrophage Polarization and Macrophage-Derived miRNAs in Pulmonary Fibrosis
Authors: Kishore Amit , Petrek Martin
Published: August 2021

This mini-review summarizes the current evidence for the role of macrophage activation and polarization in inflammation and immune response pertinent to interstitial lung disease, specifically pulmonary fibrosis. In the fibrosing lung, the production and function of inflammatory and fibrogenic mediators involved in the disease development have been reported to be regulated by the effects of polarized M1/M2 macrophage populations. The M1 and M2 macrophage phenotypes were suggested to correspond with the pro-inflammatory and pro-fibrogenic signatures, respectively. These responses towards tissue injury followed by the development and progression of lung fibrosis are further regulated by macrophage-derived microRNAs (miRNAs). Besides cellular miRNAs, extracellular exosomal-miRNAs derived from M2 macrophages have also been proposed to promote the progression of pulmonary fibrosis. In a future perspective, harnessing the noncoding miRNAs with a key role in the macrophage polarization is, therefore, suggested as a promising therapeutic strategy for this debilitating disease.
An Explorative Study on Monocyte Reprogramming in the Context of Periodontitis In Vitro and In Vivo
Authors: Noz Marlies P. , Plachokova Adelina S. , Smeets Esther M.M. , Aarntzen Erik H. J. G. , Bekkering Siroon , Vart Prya , Joosten Leo A. B. , Netea Mihai G. , Riksen Niels P.
Published: August 2021

Aims

Periodontitis is an independent risk factor for cardiovascular disease, but the mechanistic link is not fully understood. In atherosclerotic cardiovascular disease, monocytes can adopt a persistent hyperresponsive phenotype, termed trained immunity. We hypothesized that periodontitis-associated bacteria can induce trained immunity in monocytes, which subsequently accelerate atherosclerosis development.

Materials and Methods

We combined in vitro experiments on human primary monocytes and in vivo techniques in patients with periodontitis to test this hypothesis. Adherent peripheral blood mononuclear cells (PBMCs) were transiently exposed in vitro to Porphyromonas gingivalis for 24 hours, and restimulated with lipopolysaccharide (LPS) or Pam3CysK4 (P3C) six days later, to measure interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) production. In an exploratory observational study, patients with severe periodontitis (63 ± 6 years, n=14) and control subjects with no-to-mild periodontitis (54 ± 10 years, n=14) underwent venipuncture and 2’-deoxy-2’-[18F]fluoro-D-glucose positron-emission-tomography ([18F]FDG PET/CT) scanning.

Results

When adherent peripheral blood mononuclear cells (PBMCs) were transiently exposed in vitro to Porphyromonas gingivalis for 24 hours, and restimulated with LPS or P3C six days later, IL-6 and TNFα production was significantly increased (TNFα/P3C, p<0.01). Circulating leukocytes, IL-6 and interleukin-1 receptor antagonist (IL-1Ra) concentrations were generally higher in patients compared to controls (leukocytes: p<0.01; IL-6: p=0.08; IL-1Ra: p=0.10). Cytokine production capacity in PBMCs after 24h stimulation revealed no differences between groups. [18F]FDG PET/CT imaging showed a trend for increased [18F]FDG-uptake in the periodontium [mean standard uptake value (SUVmean), p=0.11] and in femur bone marrow (SUVmean, p=0.06), but no differences were observed for vascular inflammation. Positive correlations between severity of periodontitis, measured by The Dutch Periodontal Screening Index and pocket depth, with circulating inflammatory markers and tissue inflammation were found.

Conclusions

P. gingivalis induces long-term activation of human monocytes in vitro (trained immunity). Patients with severe periodontitis did have signs of increased systemic inflammation and hematopoietic tissue activation. However, their circulating monocytes did not show a hyperresponsive phenotype. Together we suggest that trained immunity might contribute to local periodontal inflammation which warrants further investigation.
Identification of Novel Low-Density Neutrophil Markers Through Unbiased High-Dimensional Flow Cytometry Screening in Non-Small Cell Lung Cancer Patients
Authors: Valadez-Cosmes Paulina , Maitz Kathrin , Kindler Oliver , Raftopoulou Sofia , Kienzl Melanie , Santiso Ana , Mihalic Zala Nikita , Brcic Luka , Lindenmann Jörg , Fediuk Melanie , Pichler Martin , Schicho Rudolf , Houghton A. McGarry , Heinemann Akos , Kargl Julia
Published: August 2021

Neutrophils have been described as a phenotypically heterogeneous cell type that possess both pro- and anti-tumor properties. Recently, a subset of neutrophils isolated from the peripheral blood mononuclear cell (PBMC) fraction has been described in cancer patients. These low-density neutrophils (LDNs) show a heterogeneous maturation state and have been associated with pro-tumor properties in comparison to mature, high-density neutrophils (HDNs). However, additional studies are necessary to characterize this cell population. Here we show new surface markers that allow us to discriminate between LDNs and HDNs in non-small cell lung cancer (NSCLC) patients and assess their potential as diagnostic/prognostic tool. LDNs were highly enriched in NSCLC patients (median=20.4%, range 0.3-76.1%; n=26) but not in healthy individuals (median=0.3%, range 0.1-3.9%; n=14). Using a high-dimensional human cell surface marker screen, we identified 12 surface markers that were downregulated in LDNs when compared to HDNs, while 41 surface markers were upregulated in the LDN subset. Using flow cytometry, we confirmed overexpression of CD36, CD41, CD61 and CD226 in the LDN fraction. In summary, our data support the notion that LDNs are a unique neutrophil population and provide novel targets to clarify their role in tumor progression and their potential as diagnostic and therapeutic tool.
Immune Checkpoints Expression in Chronic Lung Allograft Rejection
Authors: Righi Ilaria , Vaira Valentina , Morlacchi Letizia Corinna , Croci Giorgio Alberto , Rossetti Valeria , Blasi Francesco , Ferrero Stefano , Nosotti Mario , Rosso Lorenzo , Clerici Mario
Published: August 2021

Chronic lung allograft dysfunction (CLAD) is the main cause of poor survival and low quality of life of lung transplanted patients. Several studies have addressed the role of dendritic cells, macrophages, T cells, donor specific as well as anti-HLA antibodies, and interleukins in CLAD, but the expression and function of immune checkpoint molecules has not yet been analyzed, especially in the two CLAD subtypes: BOS (bronchiolitis obliterans syndrome) and RAS (restrictive allograft syndrome). To shed light on this topic, we conducted an observational study on eight consecutive grafts explanted from patients who received lung re-transplantation for CLAD. The expression of a panel of immune molecules (PD1/CD279, PDL1/CD274, CTLA4/CD152, CD4, CD8, hFoxp3, TIGIT, TOX, B-Cell-Specific Activator Protein) was analyzed by immunohistochemistry in these grafts and in six control lungs. Results showed that RAS compared to BOS grafts were characterized by 1) the inversion of the CD4/CD8 ratio; 2) a higher percentage of T lymphocytes expressing the PD-1, PD-L1, and CTLA4 checkpoint molecules; and 3) a significant reduction of exhausted PD-1-expressing T lymphocytes (PD-1pos/TOXpos) and of exhausted Treg (PD-1pos/FOXP3pos) T lymphocytes. Results herein, although being based on a limited number of cases, suggest a role for checkpoint molecules in the development of graft rejection and offer a possible immunological explanation for the worst prognosis of RAS. Our data, which will need to be validated in ampler cohorts of patients, raise the possibility that the evaluation of immune checkpoints during follow-up offers a prognostic advantage in monitoring the onset of rejection, and suggest that the use of compounds that modulate the function of checkpoint molecules could be evaluated in the management of chronic rejection in LTx patients.
MICA and KIR: Immunogenetic Factors Influencing Left Ventricular Systolic Dysfunction and Digestive Clinical Form of Chronic Chagas Disease
Authors: Ayo Christiane Maria , Bestetti Reinaldo Bulgarelli , de Campos Junior Eumildo , Ronchi Luiz Sérgio , Borim Aldenis Albaneze , Brandão Cinara Cássia , de Matttos Luiz Carlos
Published: August 2021

Tissue damage observed in the clinical forms of chronic symptomatic Chagas disease seems to have a close relationship with the intensity of the inflammatory process. The objective of this study was to investigate whether the MICA (MHC class I-related chain A) and KIR (killer cell immunoglobulin-like receptors) polymorphisms are associated with the cardiac and digestive clinical forms of chronic Chagas disease. Possible influence of these genes polymorphisms on the left ventricular systolic dysfunction (LVSD) in patients with chronic Chagas heart disease was also evaluated. This study enrolled 185 patients with positive serology for Trypanosoma cruzi classified according to the clinical form of the disease: cardiac (n=107) and digestive (n=78). Subsequently, patients with the cardiac form of the disease were sub-classified as with LVSD (n=52) and without LVSD (n=55). A control group was formed of 110 healthy individuals. Genotyping was performed by polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP). Statistical analyzes were carried out using the Chi-square test and odds ratio with 95% confidence interval was also calculated to evaluate the risk association. MICA-129 allele with high affinity for the NKG2D receptor was associated to the LVSD in patients with CCHD. The haplotype MICA*008~HLA-C*06 and the KIR2DS2-/KIR2DL2-/KIR2DL3+/C1+ combination were associated to the digestive clinical form of the disease. Our data showed that the MICA and KIR polymorphisms may exert a role in the LVSD of cardiac patients, and in digestive form of Chagas disease.
Long Noncoding RNA RP11-115N4.1 Promotes Inflammatory Responses by Interacting With HNRNPH3 and Enhancing the Transcription of HSP70 in Unexplained Recurrent Spontaneous Abortion
Authors: Liu Meilan , Sun Xiaoyue , Zhu Liqiong , Zhu Menglan , Deng Kewen , Nie Xiaolu , Mo Hanjie , Du Tao , Huang Bingqian , Hu Lihao , Liang Liuhong , Wang Dongyan , Luo Yinger , Yi Jinling , Zhang Jianping , Zhong Xingming , Cao Chunwei , Chen Hui
Published: August 2021

Background

Unexplained recurrent spontaneous abortion (URSA) is a common pregnancy complication and the etiology is unknown. URSA-associated lncRNAs are expected to be potential biomarkers for diagnosis, and might be related to the disease pathogenesis.

Objective

To investigate differential lncRNAs in peripheral blood of non-pregnant URSA patients and matched healthy control women and to explore the possible mechanism of differential lncRNAs leading to URSA.

Methods

We profiled lncRNAs expression in peripheral blood from 5 non-pregnant URSA patients and 5 matched healthy control women by lncRNA microarray analysis. Functions of URSA-associated lncRNAs were further investigated in vitro.

Results

RP11-115N4.1 was identified as the most differentially expressed lncRNA which was highly upregulated in peripheral blood of non-pregnant URSA patients (P = 3.63E-07, Fold change = 2.96), and this dysregulation was further validated in approximately 26.67% additional patients (4/15). RP11-115N4.1 expression was detected in both lymphocytes and monocytes of human peripheral blood, and in vitro overexpression of RP11-115N4.1 decreased cell proliferation in K562 cells significantly. Furthermore, heat-shock HSP70 genes (HSPA1A and HSPA1B) were found to be significantly upregulated upon RP11-115N4.1 overexpression by transcriptome analysis (HSPA1A (P = 4.39E-08, Fold change = 4.17), HSPA1B (P = 2.26E-06, Fold change = 2.99)). RNA pull down and RNA immunoprecipitation assay (RIP) analysis demonstrated that RP11-115N4.1 bound to HNRNPH3 protein directly, which in turn activate heat-shock proteins (HSP70) analyzed by protein-protein interaction and HNRNPH3 knockdown assays. Most importantly, the high expression of HSP70 was also verified in the serum of URSA patients and the supernatant of K562 cells with RP11-115N4.1 activation, and HSP70 in supernatant can exacerbate inflammatory responses in monocytes by inducing IL-6, IL-1β, and TNF-α and inhibit the migration of trophoblast cells, which might associate with URSA.

Conclusion

Our results demonstrated that the activation of RP11-115N4.1 can significantly increase the protein level of HSP70 via binding to HNRNPH3, which may modulate the immune responses and related to URSA. Moreover, RP11-115N4.1 may be a novel etiological biomarker and a new therapeutic target for URSA.