bluuebunny/crossref_metadata_2025 huggingface dataset:
Rutaecarpine Inhibits Doxorubicin-Induced Oxidative Stress and Apoptosis by Activating AKT Signaling Pathway
Authors: Liao Zi-Qi , Jiang Yi-Nong , Su Zhuo-Lin , Bi Hai-Lian , Li Jia-Tian , Li Cheng-Lin , Yang Xiao-Lei , Zhang Ying , Xie Xin
Published: January 2022

Patients with cancer who receive doxorubicin (DOX) treatment can experience cardiac dysfunction, which can finally develop into heart failure. Oxidative stress is considered the most important mechanism for DOX-mediated cardiotoxicity. Rutaecarpine (Rut), a quinazolinocarboline alkaloid extracted from Evodia rutaecarpa was shown to have a protective effect on cardiac disease. The purpose of this study is to investigate the role of Rut in DOX-induced cardiotoxicity and explore the underlying mechanism. Intravenous injection of DOX (5 mg/kg, once a week) in mice for 4 weeks was used to establish the cardiotoxic model. Echocardiography and pathological staining analysis were used to detect the changes in structure and function in the heart. Western blot and real-time PCR analysis were used to detect the molecular changes. In this study, we found that DOX time-dependently decreased cardiac function with few systemic side effects. Rut inhibited DOX-induced cardiac fibrosis, reduction in heart size, and decrease in heart function. DOX-induced reduction in superoxide dismutase (SOD) and glutathione (GSH), enhancement of malondialdehyde (MDA) was inhibited by Rut administration. Meanwhile, Rut inhibited DOX-induced apoptosis in the heart. Importantly, we further found that Rut activated AKT or nuclear factor erythroid 2-related factor 2 (Nrf-2) which further upregulated the antioxidant enzymes such as heme oxygenase-1 (HO-1) and GSH cysteine ligase modulatory subunit (GCLM) expression. AKT inhibitor (AKTi) partially inhibited Nrf-2, HO-1, and GCLM expression and abolished the protective role of Rut in DOX-induced cardiotoxicity. In conclusion, this study identified Rut as a potential therapeutic agent for treating DOX-induced cardiotoxicity by activating AKT.
Isolated Diastolic Hypertension and Risk of Cardiovascular Events: A Systematic Review and Meta-Analysis of Cohort Studies With 489,814 Participants
Authors: Huang Mingyan , Long Linzi , Tan Ling , Shen Aling , Deng Mi , Peng Yuxuan , Yang Wenwen , Li Hongzheng , Wei Yue , Li Meng , Liao Feifei , Liu Chao , Lu Aimei , Qu Hua , Fu Changgeng , Chen Keji
Published: January 2022

Background:The association between isolated diastolic hypertension (IDH) and cardiovascular events has been inconsistently reported. This meta-analysis of cohort studies was designed to investigate the effect of the 2018 European Society of Cardiology (ESC) definition of IDH on the risk of composite cardiovascular events, cardiovascular mortality, all-cause mortality, and all strokes including ischemic stroke (IS) and hemorrhagic stroke (HS).

Methods:PubMed, Embase, the Cochrane Library, and Web of Science were searched from inception to July 6, 2021. Cohort studies that investigated the association between IDH and cardiovascular events risk, compared to normotension, were included. Pooled hazard ratios (HRs) and 95% CIs were calculated using a random-effects models and heterogeneity was evaluated usingQ-test andI2statistic. The robustness of the associations was identified using sensitivity analysis. The methodological quality of the studies was assessed using the Newcastle–Ottawa scale. Publication bias was assessed using funnel plot, trim-and-fill method, Begg's test, and Egger's test.

Results:A total of 15 cohort studies (13 articles) including 489,814 participants were included in this meta-analysis. The follow-up period ranged from 4.3 to 29 years. IDH was significantly associated with an increased risk of composite cardiovascular events (HR 1.28, 95% CI: 1.07–1.52,p= 0.006), cardiovascular mortality (HR 1.45, 95% CI: 1.07–1.95,p= 0.015), all strokes (HR 1.44, 95% CI: 1.04–2.01,p= 0.03), and HS (HR 1.64, 95% CI: 1.18–2.29,p= 0.164), but not associated with all-cause mortality (HR 1.20, 95% CI: 0.97–1.47,p= 0.087) and IS (HR 1.56, 95% CI: 0.87–2.81,p= 0.137). Subgroup analysis further indicated that IDH in the younger patients (mean age ≤ 55 years) and from Asia were significantly associated with an increased risk of composite cardiovascular events, while the elderly patients (mean age ≥ 55 years), Americans, and Europeans were not significantly associated with an increased risk of composite cardiovascular events.

Conclusion:This meta-analysis provides evidence that IDH defined using the 2018 ESC criterion is significantly associated with an increased risk of composite cardiovascular events, cardiovascular mortality, all strokes and HS, but not significantly associated with all-cause death and IS. These findings also emphasize the importance for patients with IDH to have their blood pressure within normal, especially in the young adults and Asians.

Trial Registration:PROSPERO, Identifier: CRD42021254108.
Origin and Pathways of Dissolved Organic Carbon in a Small Catchment in the Lena River Delta
Authors: Stolpmann Lydia , Mollenhauer Gesine , Morgenstern Anne , Hammes Jens S. , Boike Julia , Overduin Pier Paul , Grosse Guido
Published: January 2022

The Arctic is rich in aquatic systems and experiences rapid warming due to climate change. The accelerated warming causes permafrost thaw and the mobilization of organic carbon. When dissolved organic carbon is mobilized, this DOC can be transported to aquatic systems and degraded in the water bodies and further downstream. Here, we analyze the influence of different landscape components on DOC concentrations and export in a small (6.45 km2) stream catchment in the Lena River Delta. The catchment includes lakes and ponds, with the flow path from Pleistocene yedoma deposits across Holocene non-yedoma deposits to the river outlet. In addition to DOC concentrations, we use radiocarbon dating of DOC as well as stable oxygen and hydrogen isotopes (δ18O and δD) to assess the origin of DOC. We find significantly higher DOC concentrations in the Pleistocene yedoma area of the catchment compared to the Holocene non-yedoma area with medians of 5 and 4.5 mg L−1 (p < 0.05), respectively. When yedoma thaw streams with high DOC concentration reach a large yedoma thermokarst lake, we observe an abrupt decrease in DOC concentration, which we attribute to dilution and lake processes such as mineralization. The DOC ages in the large thermokarst lake (between 3,428 and 3,637 14C y BP) can be attributed to a mixing of mobilized old yedoma and Holocene carbon. Further downstream after the large thermokarst lake, we find progressively younger DOC ages in the stream water to its mouth, paired with decreasing DOC concentrations. This process could result from dilution with leaching water from Holocene deposits and/or emission of ancient yedoma carbon to the atmosphere. Our study shows that thermokarst lakes and ponds may act as DOC filters, predominantly by diluting incoming waters of higher DOC concentrations or by re-mineralizing DOC to CO2 and CH4. Nevertheless, our results also confirm that the small catchment still contributes DOC on the order of 1.2 kg km−2 per day from a permafrost landscape with ice-rich yedoma deposits to the Lena River.
Variability in Soil Moisture by Natural and Artificial Snow: A Case Study in Mt. Balwang Area, Gangwon-do, South Korea
Authors: Nyamgerel Yalalt , Jung Hyejung , Koh Dong-Chan , Ko Kyung-Seok , Lee Jeonghoon
Published: January 2022

Soil moisture is an important variable for understanding hydrological processes, and the year-round monitoring of soil moisture and temperature reflect the variations induced by snow cover and its melt. Herein, we monitored the soil moisture and temperature in high (two sites) and low (two sites) elevation regions with groundwater sampling near the Mt. Balwang area in Gangwon-do, South Korea from Sep 2020 to May 2021. This study aims to investigate the temporal and spatial variations in soil moisture and temperature due to snow (natural and artificial snow) and its melt. A ski resort has been operating in this area and has been producing artificial snow during winter periods; thus, the spring snowmelt comprises both natural and artificial snow. The effect of soil freezing and thawing, wind conditions, vegetation covers, the timing and intensity of snow cover and snowmelt were differed in the monitoring sites. The high elevation sites 1 and 2 exhibit the relatively longer and consistent snow cover than the low elevation sites. Particularly, site 2 show late (May 8) snow melting even this site is in south slope of the Mt. Balwang. The relatively steady and moist soil layers at sites 1, 2, and 3 during the warm period can be considered as influential points to groundwater recharge. Moreover, the differences between the mean δ18O (−9.89‰) of the artificial snow layers and other samples were low: in the order of surface water (0.04‰) >groundwater (−0.66 and −1.01‰) >natural snow (1.34 and −3.80‰). This indicates that the imprint of artificial snow derived from surface water and with decreasing amount of natural snow around the Mt. Balwang region, the results support the assumption that the potential influence of artificial snowmelt on groundwater quality. This study helps to understand the snow dynamic and its influence on the hydrological processes in this region by combining the hydro-chemical and isotopic analysis.
Depositional Models of Deep-Water Gravity-Flow in Lacustrine Basin and Its Petroleum Geological Significance—A Case Study of Chang 6 Oil Group in Heshui Area, Ordos Basin, China
Authors: Yang Yiming , Peng Jun , Chen Zhaobing , Zhou Xiaoying , Zeng Yao , Wang Yubin , Wang Xueying
Published: January 2022

Gravity-flow can carry a large number of sediments and organic matters from shallow water to deep lakes with its strong transporting energy, directly or indirectly facilitating the formation of deep-water tight reservoirs and shale reservoirs. Therefore, studying the genetic types, dynamic mechanisms, and depositional models of gravity-flow deposits is essential in the exploration of unconventional petroleum in large lacustrine basins. This research studied the genetic types, dynamic mechanisms, and sedimentary models of the gravity-flow deposits of the Chang 6 oil group in the Heshui Area, Ordos Basin, China, aiming to reveal its petroleum geological significance. Core observation, microscopic thin section identification, particle size analysis, and determination of rare earth elements were carried out. As a result, three types of gravity-flow deposits are detected, namely, slide-slump, sandy debris flow, and turbidity current. A certain slope gradient in bed form is the necessary geomorphic condition for gravity flow formation, and determines its development level, distribution range, and flow transformation efficiency. Sufficient provenance lays the material foundation and determines its depositional composition and development type. Other factors include earthquakes, volcanoes, and floods, which serve as triggering forces. In addition, fragmentation, liquefaction, and fluid mixing are the main dynamic mechanisms driving flow transformation. Based on the flow type of gravity flow, particle size characteristics, gravity-flow transformation relations, development mechanism, and spatial distribution pattern, we distinguished two depositional gravity-flow models, i.e., slump turbidite body and sublacustrine fan. Re-portrait the spatial distribution of deep-water gravity flow in the study area. From the perspective of sedimentology, explain the genesis of sand bodies in the northeast and southwest. The sandy debris flow in the middle fan braided channel microfacies of the sublacustrine fan sways the development of thick massive sand bodies in the study area. Hybrid event beds formed by the fluid transformation in a slump turbidite are the potential dessert area for deep-water tight oil and gas.
Mining Hazards to the Safety of Segment Lining for Tunnel Boring Machine Inclined Tunnels
Authors: Zhuo Hui , Xie Dan , Sun Jinglai , Shi Xiaomeng
Published: January 2022

The segment lining is a new type of support structure for mining tunnels. The disturbance of coal excavation leads to the deformation of segment lining and has great hazards to the safety of the tunnels. Based on the tunnel boring machine (TBM) inclined tunnels in Xinjie mine, the ultimate span L0 of the rock beam on the top slab of the coal seam was calculated according to the bending (tension) damage theory. A numerical model was built to simulate the bottom area of the inclined tunnels. During the coal mining, the additional displacements and additional stresses of the segment lining were analyzed, and then the safety factors of the support structure were calculated. Finally, the width of the coal pillar to protect the inclined tunnels was determined. The results showed that the ultimate span of the rock beam on the top of the coal seam is 31.7 m, the deformation of the inclined tunnel has a fish-belly shape, and the deformation leads to the increase of maximum axial force and bending moment. For the inclined tunnels in Xinjie coalmine, a total width of 91.3 m of coal pillar must be reserved to keep the safety factor of the structure higher than 2.0 and prevent the inclined tunnels from the mining hazards.
Changes in Teacher Burnout and Self-Efficacy During the COVID-19 Pandemic: Interrelations and e-Learning Variables Related to Change
Authors: Weißenfels Marie , Klopp Eric , Perels Franziska
Published: January 2022

Although the reciprocal relationship of teacher burnout and teacher self-efficacy (TSE) is well documented, the literature still lacks studies investigating their (latent) changes and interrelations of change over time. By applying a latent change regression model in our study, we aimed to contribute to this research gap by examining changes in burnout and their relations to changes in TSE during the COVID-19 pandemic—a very challenging time for teachers. As the implementation of digital learning material played a major role during the pandemic, we were also interested if attitudes and self-efficacy toward e-Learning were related to changes in burnout and TSE. Our sample consisted of 92 German in-service teachers who completed a questionnaire twice during the 2019–2020 school year. Our main findings are that the burnout components depersonalization and lack of accomplishment significantly increased from the pre- to post-COVID-19 outbreak, whereas emotional exhaustion did not. Changes in burnout were negatively correlated to changes in TSE, but we found little evidence for relations of change in burnout and TSE with variables concerning e-Learning. Our findings indicate that the challenge was not the work overload but rather a lack of resources. Implications for research and practice are discussed.
Emerging Insights Into the Role of Epigenetics and Gut Microbiome in the Pathogenesis of Graves’ Ophthalmopathy
Authors: Wang Yan , Ma Xiao-Min , Wang Xin , Sun Xin , Wang Ling-Jun , Li Xin-Qi , Liu Xiao-Yan , Yu Hong-Song
Published: January 2022

Graves’ Ophthalmopathy (GO) is an organ-specific autoimmune disease that is often characterized by infiltration of orbital tissues and is considered as the most common extra-thyroid manifestation of Graves’ disease (GD). Although genetic susceptibility has been found to be critical for the phenotype of GO, the associated risk alleles in a single gene are generally insufficient to cause the disease. Accruing evidence has shown that epigenetic disorders can act as the potentially missing link between genetic risk and clinically significant disease development. Abnormal epigenetic modifications can lead to pro-inflammatory cascades and activation of orbital fibroblasts (OFs) by promoting the various inflammatory response pathways and regulating the diverse signaling molecules that are involved in the fibrogenesis and adipogenesis, thereby leading to the significant expansion of orbital tissues, fibrosis and inflammation infiltration. Additionally, emerging evidence has shown that the gut microbiome can possibly drive the pathogenesis of GO by influencing the secretion of Thyrotropin receptor antibody (TRAb) and T-helper 17 (Th17)/regulatory T cells (Treg) imbalance. This paper describes the latest epigenetic research evidence and progress made in comprehending the mechanisms of GO development, such as DNA methylation, histone modification, non-coding RNAs, and the gut microbiome.
Considerations for the Accurate Measurement of Incident Photon to Current Efficiency in Photoelectrochemical Cells
Authors: Ellis David S. , Piekner Yifat , Grave Daniel A. , Schnell Patrick , Rothschild Avner
Published: January 2022

In this paper we review some of the considerations and potential sources of error when conducting Incident Photon to Current Efficiency (IPCE) measurements, with focus on photoelectrochemical (PEC) cells for water splitting. The PEC aspect introduces challenges for accurate measurements often not encountered in dry PV cells. These can include slow charge transfer dynamics and, depending on conditions (such as a white light bias, which is important for samples with non-linear response to light intensity), possible composition changes, mostly at the surface, that a sample may gradually undergo as a result of chemical interactions with the aqueous electrolyte. These can introduce often-overlooked dependencies related to the timing of the measurement, such as a slower measurement requirement in the case of slow charge transfer dynamics, to accurately capture the steady-state response of the system. Fluctuations of the probe beam can be particularly acute when a Xe lamp with monochromator is used, and longer scanning times also allow for appreciable changes in the sample environment, especially when the sample is under realistically strong white light bias. The IPCE measurement system and procedure need to be capable of providing accurate measurements under specific conditions, according to sample and operating requirements. To illustrate these issues, complications, and solution options, we present example measurements of hematite photoanodes, leading to the use of a motorized rotating mirror stage to solve the inherent fluctuation and drift-related problems. For an example of potential pitfalls in IPCE measurements of metastable samples, we present measurements of BiVO4 photoanodes, which had changing IPCE spectral shapes under white-light bias.
Preparation of Adsorbents by Pyrolysis of Sludge Mixed With Steel Slag and Study on Adsorption of Chromium Ions in Water
Authors: Qi Xiaowen , Zhou Enze , Wu Xuefei , Luo Siyi , Song Yanggang
Published: January 2022

In this study, the dewatered sludge from the sewage plant and the open-hearth steel slag of the steel plant are used as raw materials. As two wastes, they were mixed and pyrolyzed to prepare a composite absorbent. Further, the adsorption mechanism of the adsorbent to chromium ions in the sewage is explored. The pyrolysis reaction behavior of sludge mixed with steel slag was studied by the thermogravimetric analysis technology. SEM, BET, and XPS were used to analyze the specific surface area, pore size distribution, and pore structure characteristics of pyrolysis products, respectively. Moreover, a comprehensive analysis of the adsorbent was carried out for the adsorption mechanism of hexavalent chromium ions. The results show that the addition of steel slag promotes the pyrolysis of the sludge in each stage. When the content of steel slag is 80%, the increases of reaction rate are the most obvious with the largest increase of weight loss rate in each stage. The SEM results show that the enrichment of sludge on metal oxides is enhanced in the high-temperature range (600–700°C). Besides, when the content of steel slag is 40–60%, the mixture’s growth rate of the specific surface area can reach 600% and the growth rate of total pore volume can reach 350% (the situations of sludge as the baseline). Regarding the measurement of Cr(VI), the adsorption rate of the steel-slag solution is 50.93% and that of the sludge solution is 69%. However, the adsorption rate can be increased to 95% when the steel slag and sludge were mixed as an adsorption solution. In conclusion, the adsorption mechanism of Cr(VI) by additives is controlled by both physical and chemical processes. The present study provides a theoretical basis and technical support for the scientific and reasonable utilization of sludge and steel slag.
Do Microbiota in the Soil Affect Embryonic Development and Immunocompetence in Hatchling Reptiles?
Authors: Brown Gregory P. , Shine Richard
Published: January 2022

Reptile eggs develop in intimate association with microbiota in the soil, raising the possibility that embryogenesis may be affected by shifts in soil microbiota caused by anthropogenic disturbance, translocation of eggs for conservation purposes, or laboratory incubation in sterile media. To test this idea we incubated eggs of keelback snakes (Tropidonophis mairii, Colubridae) in untreated versus autoclaved soil, and injected lipopolysaccharide (LPS) into the egg to induce an immune response in the embryo. Neither treatment modified hatching success, water uptake, incubation period, or white-blood-cell profiles, but both treatments affected hatchling size. Eggs incubated on autoclaved soil produced smaller hatchlings than did eggs on untreated soil, suggesting that heat and/or pressure treatment decrease the soil’s suitability for incubation. Injection of LPS reduced hatchling size, suggesting that the presence of pathogen cues disrupts embryogenesis, possibly by initiating immune reactions unassociated with white-blood-cell profiles. Smaller neonates had higher ratios of heterophils to leucocytes, consistent with higher stress in smaller snakes, or body-size effects on investment into different types of immune cells. Microbiota in the incubation medium thus can affect viability-relevant phenotypic traits of hatchling reptiles. We need further studies to explore the complex mechanisms and impacts of environmental conditions on reptilian embryogenesis.
A Coordinated, Risk-Based, National Forest Biosecurity Surveillance Program for Australian Forests
Authors: Carnegie Angus J. , Tovar Francisco , Collins Susie , Lawson Simon A. , Nahrung Helen F.
Published: January 2022

Australia has a comprehensive plant biosecurity system, with the Australian Government responsible for pre-border (e.g., off-shore compliance) and border (e.g., import inspections) activities, while state governments undertake a variety of post-border activities (e.g., post-border surveillance, management of pest incursions, and regulation of pests) designed to reduce alien pest and pathogen arrival and establishment. Once an alien pest or pathogen has established and spread, its management becomes the responsibility of the land manager. There has been a growing understanding among plant industries of the need to be more engaged in post-border biosecurity activities, including resourcing and undertaking early detection surveillance and contingency planning. Here we summarize Australia’s broader plant biosecurity system along with current forest-specific biosecurity surveillance activities. We describe the development of a proposed forest biosecurity partnership between the Australian Government, state governments and the forest sector to establish a post-border, risk-based National Forest Pest Surveillance Program. We outline why there is a recognized need for such a program, how it would improve biosecurity outcomes in relation to forests, its component activities, and key stakeholders and beneficiaries.
A Novel Inflammatory-Related Gene Signature Based Model for Risk Stratification and Prognosis Prediction in Lung Adenocarcinoma
Authors: Zhai Wen-Yu , Duan Fang-Fang , Chen Si , Wang Jun-Ye , Lin Yao-Bin , Wang Yi-Zhi , Rao Bing-Yu , Zhao Ze-Rui , Long Hao
Published: January 2022

Inflammation is an important hallmark of cancer and plays a role in both neogenesis and tumor development. Despite this, inflammatory-related genes (IRGs) remain to be poorly studied in lung adenocarcinoma (LUAD). We aim to explore the prognostic value of IRGs for LUAD and construct an IRG-based prognosis signature. The transcriptomic profiles and clinicopathological information of patients with LUAD were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Least absolute shrinkage and selection operator (LASSO) analysis and multivariate Cox regression were applied in the TCGA set to generate an IRG risk signature. LUAD cases with from the GSE31210 and GSE30219 datasets were used to validate the predictive ability of the signature. Analysis of the TCGA cohort revealed a five-IRG risk signature consisting of EREG, GPC3, IL7R, LAMP3, and NMUR1. This signature was used to divide patients into two risk groups with different survival rates. Multivariate Cox regression analysis verified that the risk score from the five-IRG signature negatively correlated with patient outcome. A nomogram was developed using the IRG risk signature and stage, with C-index values of 0.687 (95% CI: 0.644–0.730) in the TCGA training cohort, 0.678 (95% CI: 0.586–0.771) in GSE30219 cohort, and 0.656 (95% CI: 0.571–0.740) in GSE30219 cohort. Calibration curves were consistent between the actual and the predicted overall survival. The immune infiltration analysis in the TCGA training cohort and two GEO validation cohorts showed a distinctly differentiated immune cell infiltration landscape between the two risk groups. The IRG risk signature for LUAD can be used to predict patient prognosis and guide individual treatment. This risk signature is also a potential biomarker of immunotherapy.
Stress Conditions Modulate the Chromatin Interactions Network in Arabidopsis
Authors: Yadav Vikash Kumar , Singh Swadha , Yadav Amrita , Agarwal Neha , Singh Babita , Jalmi Siddhi Kashinath , Yadav Vrijesh Kumar , Tiwari Vipin Kumar , Kumar Verandra , Singh Raghvendra , Sawant Samir Vishwanath
Published: January 2022

Stresses have been known to cause various responses like cellular physiology, gene regulation, and genome remodeling in the organism to cope and survive. Here, we assessed the impact of stress conditions on the chromatin-interactome network of Arabidopsis thaliana. We identified thousands of chromatin interactions in native as well as in salicylic acid treatment and high temperature conditions in a genome-wide fashion. Our analysis revealed the definite pattern of chromatin interactions and stress conditions could modulate the dynamics of chromatin interactions. We found the heterochromatic region of the genome actively involved in the chromatin interactions. We further observed that the establishment or loss of interactions in response to stress does not result in the global change in the expression profile of interacting genes; however, interacting regions (genes) containing motifs for known TFs showed either lower expression or no difference than non-interacting genes. The present study also revealed that interactions preferred among the same epigenetic state (ES) suggest interactions clustered the same ES together in the 3D space of the nucleus. Our analysis showed that stress conditions affect the dynamics of chromatin interactions among the chromatin loci and these interaction networks govern the folding principle of chromatin by bringing together similar epigenetic marks.
TGFβ2 Induces the Soluble Isoform of CTLA-4 – Implications for CTLA-4 Based Checkpoint Inhibitor Antibodies in Malignant Melanoma
Authors: Khanolkar Rahul C. , Zhang Chu , Al-Fatyan Farah , Lawson Linda , Depasquale Ivan , Meredith Fiona M. , Muller Frank , Nicolson Marianne , Dahal Lekh Nath , Abu-Eid Rasha , Rajpara Sanjay , Barker Robert Norman , Ormerod Anthony D. , Ward Frank James
Published: January 2022

Malignant melanoma is an aggressive form of cancer, which can be treated with anti-CTLA-4 and anti-PD-1 checkpoint inhibitor antibodies but while anti-CTLA-4 antibodies have clear benefits for some patients with melanoma, productive responses are difficult to predict and often associated with serious immune related adverse events. Antibodies specific to CTLA-4 bind two major isoforms of CTLA-4 in humans, the receptor isoform and a second naturally secretable, soluble isoform - sCTLA-4. The primary aim here was to examine the effect of selectively blocking the function of sCTLA-4 on in vitro immune responses from volunteer healthy or melanoma patient PBMC samples. Addition of recombinant sCTLA-4 to healthy PBMC samples demonstrated sCTLA-4 to have immunosuppressive capacity comparable to recombinant CTLA4-Ig, partially reversible upon antibody blockade. Further, we identified a mechanistic relationship where melanoma patient TGFβ2 serum levels correlated with sCTLA-4 levels and provided the basis for a novel protocol to enhance sCTLA-4 production and secretion by T cells with TGFβ2. Finally, a comparison of selective antibody blockade of sCTLA-4 demonstrated that both healthy and melanoma patient effector cytokine responses can be significantly increased. Overall, the data support the notion that sCTLA-4 is a contributory factor in cancer immune evasion.
Pharmacological Inhibition of IRE-1 Alpha Activity in Herpes Simplex Virus Type 1 and Type 2-Infected Dendritic Cells Enhances T Cell Activation
Authors: Tognarelli Eduardo I. , Retamal-Díaz Angello , Farías Mónica A. , Duarte Luisa F. , Palomino Tomás F. , Ibañez Francisco J. , Riedel Claudia A. , Kalergis Alexis M. , Bueno Susan M. , González Pablo A.
Published: January 2022

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections are life-long and highly prevalent in the human population. These viruses persist in the host, eliciting either symptomatic or asymptomatic infections that may occur sporadically or in a recurrent manner through viral reactivations. Clinical manifestations due to symptomatic infection may be mild such as orofacial lesions, but may also translate into more severe diseases, such as ocular infections that may lead to blindness and life-threatening encephalitis. A key feature of herpes simplex viruses (HSVs) is that they have evolved molecular determinants that hamper numerous components of the host’s antiviral innate and adaptive immune system. Importantly, HSVs infect and negatively modulate the function of dendritic cells (DCs), by inhibiting their T cell-activating capacity and eliciting their apoptosis after infection. Previously, we reported that HSV-2 activates the splicing of the mRNA of XBP1, which is related to the activity of the unfolded protein response (UPR) factor Inositol-Requiring Enzyme 1 alpha (IRE-1α). Here, we sought to evaluate if the activation of the IRE-1α pathway in DCs upon HSV infection may be related to impaired DC function after infection with HSV-1 or HSV-2. Interestingly, the pharmacological inhibition of the endonuclease activity of IRE-1α in HSV-1- and HSV-2-infected DCs significantly reduced apoptosis in these cells and enhanced their capacity to migrate to lymph nodes and activate virus-specific CD4+ and CD8+ T cells. These findings suggest that the activation of the IRE-1α-dependent UPR pathway in HSV-infected DCs may play a significant role in the negative effects that these viruses exert over these cells and that the modulation of this signaling pathway may be relevant for enhancing the function of DCs upon infection with HSVs.
Comprehensive Pan-Cancer Genomic Analysis Reveals PHF19 as a Carcinogenic Indicator Related to Immune Infiltration and Prognosis of Hepatocellular Carcinoma
Authors: Zhu Zheng-yi , Tang Ning , Wang Ming-fu , Zhou Jing-chao , Wang Jing-lin , Ren Hao-zhen , Shi Xiao-lei
Published: January 2022

Background

As a crucial constituent part of Polycomb repressive complex 2, PHD finger protein 19 (PHF19) plays a pivotal role in epigenetic regulation, and acts as a critical regulator of multiple pathophysiological processes. However, the exact roles of PHF19 in cancers remain enigmatic. The present research was primarily designed to provide the prognostic landscape visualizations of PHF19 in cancers, and study the correlations between PHF19 expression and immune infiltration characteristics in tumor microenvironment.

Methods

Raw data in regard to PHF19 expression were extracted from TCGA and GEO data portals. We examined the expression patterns, prognostic values, mutation landscapes, and protein-protein interaction network of PHF19 in pan-cancer utilizing multiple databases, and investigated the relationship of PHF19 expression with immune infiltrates across TCGA-sequenced cancers. The R language was used to conduct KEGG and GO enrichment analyses. Besides, we built a risk-score model of hepatocellular carcinoma (HCC) and validated its prognostic classification efficiency.

Results

On balance, PHF19 expression was significantly higher in cancers in comparison with that in noncancerous samples. Increased expression of PHF19 was detrimental to the clinical prognoses of cancer patients, especially HCC. There were significant correlations between PHF19 expression and TMB or MSI in several cancers. High PHF19 levels were critically associated with the infiltration of myeloid-derived suppressor cells (MDSCs) and Th2 subsets of CD4+ T cells in most cancers. Enrichment analyses revealed that PHF19 participated in regulating carcinogenic processes including cell cycle and DNA replication, and was correlated with the progression of HCC. Intriguingly, GSEA suggested that PHF19 was correlated with the cellular components including immunoglobulin complex and T cell receptor complex in HCC. Based on PHF19-associated functional gene sets, an eleven-gene prognostic signature was constructed to predict HCC prognosis. Finally, we validated pan-cancer PHF19 expression, and its impacts on immune infiltrates in HCC.

Conclusion

The epigenetic related regulator PHF19 participates in the carcinogenic progression of multiple cancers, and may contribute to the immune infiltration in tumor microenvironment. Our study suggests that PHF19 can serve as a carcinogenic indicator related to prognosis in pan-cancer, especially HCC, and shed new light on therapeutics of cancers for clinicians.
Chimerism-Based Tolerance to Kidney Allografts in Humans: Novel Insights and Future Perspectives
Authors: Podestà Manuel Alfredo , Sykes Megan
Published: January 2022

Chronic rejection and immunosuppression-related toxicity severely affect long-term outcomes of kidney transplantation. The induction of transplantation tolerance – the lack of destructive immune responses to a transplanted organ in the absence of immunosuppression – could potentially overcome these limitations. Immune tolerance to kidney allografts from living donors has been successfully achieved in humans through clinical protocols based on chimerism induction with hematopoietic cell transplantation after non-myeloablative conditioning. Notably, two of these protocols have led to immune tolerance in a significant fraction of HLA-mismatched donor-recipient combinations, which represent the large majority of cases in clinical practice. Studies in mice and large animals have been critical in dissecting tolerance mechanisms and in selecting the most promising approaches for human translation. However, there are several key differences in tolerance induction between these models and humans, including the rate of success and stability of donor chimerism, as well as the relative contribution of different mechanisms in inducing donor-specific unresponsiveness. Kidney allograft tolerance achieved through durable full-donor chimerism may be due to central deletion of graft-reactive donor T cells, even though mechanistic data from patient series are lacking. On the other hand, immune tolerance attained with transient mixed chimerism-based protocols initially relies on Treg-mediated suppression, followed by peripheral deletion of donor-reactive recipient T-cell clones under antigenic pressure from the graft. These conclusions were supported by data deriving from novel high-throughput T-cell receptor sequencing approaches that allowed tracking of alloreactive repertoires over time. In this review, we summarize the most important mechanistic studies on tolerance induction with combined kidney-bone marrow transplantation in humans, discussing open issues that still need to be addressed and focusing on techniques developed in recent years to efficiently monitor the alloresponse in tolerance trials. These cutting-edge methods will be instrumental for the development of immune tolerance protocols with improved efficacy and to identify patients amenable to safe immunosuppression withdrawal.
Induction of Functional Specific Antibodies, IgG-Secreting Plasmablasts and Memory B Cells Following BCG Vaccination
Authors: Bitencourt Julia , Peralta-Álvarez Marco Polo , Wilkie Morven , Jacobs Ashley , Wright Daniel , Salman Almujri Salem , Li Shuailin , Harris Stephanie A. , Smith Steven G. , Elias Sean C. , White Andrew D. , Satti Iman , Sharpe Sally S. , O’Shea Matthew K. , McShane Helen , Tanner Rachel
Published: January 2022

Tuberculosis (TB) is a major global health problem and the only currently-licensed vaccine, BCG, is inadequate. Many TB vaccine candidates are designed to be given as a boost to BCG; an understanding of the BCG-induced immune response is therefore critical, and the opportunity to relate this to circumstances where BCG does confer protection may direct the design of more efficacious vaccines. While the T cell response to BCG vaccination has been well-characterized, there is a paucity of literature on the humoral response. We demonstrate BCG vaccine-mediated induction of specific antibodies in different human populations and macaque species which represent important preclinical models for TB vaccine development. We observe a strong correlation between antibody titers in serum versus plasma with modestly higher titers in serum. We also report for the first time the rapid and transient induction of antibody-secreting plasmablasts following BCG vaccination, together with a robust and durable memory B cell response in humans. Finally, we demonstrate a functional role for BCG vaccine-induced specific antibodies in opsonizing mycobacteria and enhancing macrophage phagocytosisin vitro, which may contribute to the BCG vaccine-mediated control of mycobacterial growth observed. Taken together, our findings indicate that the humoral immune response in the context of BCG vaccination merits further attention to determine whether TB vaccine candidates could benefit from the induction of humoral as well as cellular immunity.
Characteristics of Dysregulated Proinflammatory Cytokines and Cognitive Dysfunction in Late-Life Depression and Amnestic Mild Cognitive Impairment
Authors: Nie Jing , Fang Yuan , Chen Ying , Aidina Aisikeer , Qiu Qi , Zhao Lu , Liu Xiang , Sun Lin , Li Yun , Zhong Chuwen , Li Yuan , Li Xia
Published: January 2022

Background

Late-life depression (LLD) and amnestic mild cognitive impairment (aMCI) are two different diseases associated with a high risk of developing Alzheimer’s disease (AD). Both diseases are accompanied by dysregulation of inflammation. However, the differences and similarities of peripheral inflammatory parameters in these two diseases are not well understood.

Methods

We used Luminex assays to measure 29 cytokines simultaneously in the plasma of two large cohorts of subjects at high risk for AD (23 LLD and 23 aMCI) and 23 normal controls (NCs) in the community. Demographics and lifestyle factors were also collected. Cognitive function was evaluated with the Chinese versions of the Montreal Cognitive Assessment (C-MoCA) and neuropsychological test battery (NTB).

Results

We observed a remarkably increased level of IL-6 in the plasma and reduced levels of chemokines (CXCL11 and CCL13) in the LLD group compared with the aMCI group. The LLD group also showed lower levels of CXCL16 than the NC group. Furthermore, altered cytokine levels were associated with abnormal results in neuropsychological testing and Geriatric Depression Scale scores in both the LLD and aMCI groups. Notably, combinations of cytokines (IL-6 and CCL13) and two subitems of C-MoCA (orientation and short-term memory) generated the best area under the receiver operating characteristic curve (AUROC = 0.974).

Conclusion

A novel model based on proinflammatory cytokines and brief screening tests performs with fair accuracy in the discrimination between LLD and aMCI. These findings will give clues to provide new therapeutic targets for interventions or markers for two diseases with similar predementia syndromes.
Immunostimulatory Properties of Chemotherapy in Breast Cancer: From Immunogenic Modulation Mechanisms to Clinical Practice
Authors: Zhang Jinguo , Pan Shuaikang , Jian Chen , Hao Li , Dong Jie , Sun Qingqing , Jin Hongwei , Han Xinghua
Published: January 2022

Breast cancer (BC) is the most common malignancy among females. Chemotherapy drugs remain the cornerstone of treatment of BC and undergo significant shifts over the past 100 years. The advent of immunotherapy presents promising opportunities and constitutes a significant complementary to existing therapeutic strategies for BC. Chemotherapy as a cytotoxic treatment that targets proliferation malignant cells has recently been shown as an effective immune-stimulus in multiple ways. Chemotherapeutic drugs can cause the release of damage-associated molecular patterns (DAMPs) from dying tumor cells, which result in long-lasting antitumor immunity by the key process of immunogenic cell death (ICD). Furthermore, Off-target effects of chemotherapy on immune cell subsets mainly involve activation of immune effector cells including natural killer (NK) cells, dendritic cells (DCs), and cytotoxic T cells, and depletion of immunosuppressive cells including Treg cells, M2 macrophages and myeloid-derived suppressor cells (MDSCs). Current mini-review summarized recent large clinical trials regarding the combination of chemotherapy and immunotherapy in BC and addressed the molecular mechanisms of immunostimulatory properties of chemotherapy in BC. The purpose of our work was to explore the immune-stimulating effects of chemotherapy at the molecular level based on the evidence from clinical trials, which might be a rationale for combinations of chemotherapy and immunotherapy in BC.
Birds of a Feather Eat Plastic Together: High Levels of Plastic Ingestion in Great Shearwater Adults and Juveniles Across Their Annual Migratory Cycle
Authors: Robuck Anna R. , Hudak Christine A. , Agvent Lindsay , Emery Gwenyth , Ryan Peter G. , Perold Vonica , Powers Kevin D. , Pedersen Johanna , Thompson Michael A. , Suca Justin J. , Moore Michael J. , Harms Craig A. , Bugoni Leandro , Shield Gina , Glass Trevor , Wiley David N. , Lohmann Rainer
Published: January 2022

Limited work to date has examined plastic ingestion in highly migratory seabirds like Great Shearwaters (Ardenna gravis) across their entire migratory range. We examined 217 Great Shearwaters obtained from 2008–2019 at multiple locations spanning their yearly migration cycle across the Northwest and South Atlantic to assess accumulation of ingested plastic as well as trends over time and between locations. A total of 2328 plastic fragments were documented in the ventriculus portion of the gastrointestinal tract, with an average of 9 plastic fragments per bird. The mass, count, and frequency of plastic occurrence (FO) varied by location, with higher plastic burdens but lower FO in South Atlantic adults and chicks from the breeding colonies. No fragments of the same size or morphology were found in the primary forage fish prey, the Sand Lance (Ammodytes spp., n = 202) that supports Great Shearwaters in Massachusetts Bay, United States, suggesting the birds directly ingest the bulk of their plastic loads rather than accumulating via trophic transfer. Fourier-transform infrared spectroscopy indicated that low- and high-density polyethylene were the most common polymers ingested, within all years and locations. Individuals from the South Atlantic contained a higher proportion of larger plastic items and fragments compared to analogous life stages in the NW Atlantic, possibly due to increased use of remote, pelagic areas subject to reduced inputs of smaller, more diverse, and potentially less buoyant plastics found adjacent to coastal margins. Different signatures of polymer type, size, and category between similar life stages at different locations suggests rapid turnover of ingested plastics commensurate with migratory stage and location, though more empirical evidence is needed to ground-truth this hypothesis. This work is the first to comprehensively measure the accumulation of ingested plastics by Great Shearwaters over the last decade and across multiple locations spanning their yearly trans-equatorial migration cycle and underscores their utility as sentinels of plastic pollution in Atlantic ecosystems.
Differently Charged P (VDF-TrFE) Membranes Influence Osteogenesis Through Differential Immunomodulatory Function of Macrophages
Authors: Zhu Peijun , Lai Chunhua , Cheng Mingwei , He Yiheng , Xu Yan , Chen Jiahao , Zhou Zhengnan , Li Ping , Xu Shulan
Published: January 2022

A biomaterial-mediated immune response is a critical factor to determine the cell fate as well as the tissue-regenerative outcome. Although piezoelectric-membranes have attracted considerable interest in the field of guided bone regeneration thanks to their biomimetic electroactivity, the influence of their different surface-charge polarities on the immune-osteogenic microenvironment remains obscure. The present study aimed at investigating the interaction between piezoelectric poly (vinylidene fluoridetrifluoroethylene) [P (VDF-TrFE)] membranes with different surface polarities (negative or positive) and macrophage response, as well as their subsequent influence on osteogenesis from an immunomodulating perspective. Specifically, the morphology, wettability, crystal phase, piezoelectric performance, and surface potential of the synthetic P (VDF-TrFE) samples were systematically characterized. In addition, RAW 264.7 macrophages were seeded onto differently charged P (VDF-TrFE) surfaces, and the culture supernatants were used to supplement cultures of rat bone marrow mesenchymal stem cells (rBMSCs) on the corresponding P (VDF-TrFE) surfaces. Our results revealed that oppositely charged surfaces had different abilities in modulating the macrophage-immune-osteogenic microenvironment. Negatively charged P (VDF-TrFE), characterized by the highest macrophage elongation effect, induced a switch in the phenotype of macrophages from M0 (inactivated) to M2 (anti-inflammatory), thus promoting the osteogenic differentiation of rBMSCs by releasing anti-inflammatory cytokine IL-10. Interestingly, positively charged P (VDF-TrFE) possessed pro-inflammatory properties to induce an M1 (pro-inflammatory) macrophage-dominated reaction, without compromising the subsequent osteogenesis as expected. In conclusion, these findings highlighted the distinct modulatory effect of piezoelectric-P (VDF-TrFE) membranes on the macrophage phenotype, inflammatory reaction, and consequent immune-osteogenic microenvironment depending on their surface-charge polarity. This study provides significant insight into the design of effective immunoregulatory materials for the guided bone regeneration application.