bluuebunny/crossref_metadata_2025 huggingface dataset:
TMSB4 Overexpression Enhances the Potency of Marrow Mesenchymal Stromal Cells for Myocardial Repair
Authors: Tang Shiyuan , Fan Chengming , Iroegbu Chukwuemeka Daniel , Zhou Wenwu , Zhang Zhigong , Wu Ming , Chen Wangping , Wu Xiaoming , Peng Jun , Li Zhihong , Yang Jinfu
Published: June 2021

Objective

The actin-sequestering proteins, thymosin beta-4 (Tβ4) and hypoxia-inducible factor (HIF)-1α, are known to be associated with angiogenesis after myocardial infarction (MI). Herein, we aimed to identify the mechanism of HIF-1α induction by Tβ4 and investigate the effects of bone marrow mesenchymal stromal cells (BMMSCs) transfected with the Tβ4 gene (TMSB4) in a rat model of MI.

Methods

Rat BMMSCs were isolated, cultured, and transfected with the TMSB4 gene by using the lentivirus-mediated method. Rats with surgically induced MI were randomly divided into three groups (n = 9/group); after 1 week, the rats were injected at the heart infarcted border zone with TMSB4-overexpressed BMMSCs (BMMSC-TMSB4OE), wild-type BMMSCs that expressed normal levels of TMSB4 (BMMSC-TMSB4WT), or medium (MI). The fourth group of animals (n = 9) underwent all surgical procedures necessary for MI induction except for the ligation step (Sham). Four weeks after the injection, heart function was measured using transthoracic echocardiography. Infarct size was calculated by TTC staining, and collagen volume was measured by Masson staining. Angiogenesis in the infarcted heart area was evaluated by CD31 immunofluorescence histochemistry. In vitro experiments were carried out to observe the effect of exogenous Tβ4 on HIF-1α and explore the various possible mechanism(s).

Results

In vivo experiments showed that vascular density 4 weeks after treatment was about twofold higher in BMMSC-TMSB4OE-treated animals than in BMMSC-TMSB4WT-treated animals (p < 0.05). The cardiac function and infarct size significantly improved in both cell-treatment groups compared to controls. Notably, the cardiac function and infarct size were most prominent in BMMSC-TMSB4OE-treated animals (both p < 0.05). HIF-1α and phosphorylated HIF-1α (p-HIF-1α) in vitro were significantly enhanced by exogenous Tβ4, which was nonetheless blocked by the factor-inhibiting HIF (FIH) promoter (YC-1). The expression of prolyl hydroxylase domain proteins (PHD) was decreased upon treatment with Tβ4 and further decreased with the combined treatment of Tβ4 and FG-4497 (a specific PHD inhibitor).

Conclusion

TMSB4-transfected BMMSCs might significantly improve recovery from myocardial ischemia and promote the generation of HIF-1α and p-HIF-1α via the AKT pathway, and inhibit the degradation of HIF-1α via the PHD and FIH pathways.
Dual Characters of GH-IGF1 Signaling Pathways in Radiotherapy and Post-radiotherapy Repair of Cancers
Authors: Cheng Yunyun , Li Wanqiao , Gui Ruirui , Wang Chunli , Song Jie , Wang Zhaoguo , Wang Xue , Shen Yannan , Wang Zhicheng , Hao Linlin
Published: June 2021

Radiotherapy remains one of the most important cancer treatment modalities. In the course of radiotherapy for tumor treatment, the incidental irradiation of adjacent tissues could not be completely avoided. DNA damage is one of the main factors of cell death caused by ionizing radiation, including single-strand (SSBs) and double-strand breaks (DSBs). The growth hormone-Insulin-like growth factor 1 (GH-IGF1) axis plays numerous roles in various systems by promoting cell proliferation and inhibiting apoptosis, supporting its effects in inducing the development of multiple cancers. Meanwhile, the GH-IGF1 signaling involved in DNA damage response (DDR) and DNA damage repair determines the radio-resistance of cancer cells subjected to radiotherapy and repair of adjacent tissues damaged by radiotherapy. In the present review, we firstly summarized the studies on GH-IGF1 signaling in the development of cancers. Then we discussed the adverse effect of GH-IGF1 signaling in radiotherapy to cancer cells and the favorable impact of GH-IGF1 signaling on radiation damage repair to adjacent tissues after irradiation. This review further summarized recent advances on research into the molecular mechanism of GH-IGF1 signaling pathway in these effects, expecting to specify the dual characters of GH-IGF1 signaling pathways in radiotherapy and post-radiotherapy repair of cancers, subsequently providing theoretical basis of their roles in increasing radiation sensitivity during cancer radiotherapy and repairing damage after radiotherapy.
Using Network Pharmacology and Molecular Docking to Explore the Mechanism of Shan Ci Gu (Cremastra appendiculata) Against Non-Small Cell Lung Cancer
Authors: Wang Yan , Zhang Yunwu , Wang Yujia , Shu Xinyao , Lu Chaorui , Shao Shiliang , Liu Xingting , Yang Cheng , Luo Jingsong , Du Quanyu
Published: June 2021

Background: In recent years, the incidence and mortality rates of non-small cell lung cancer (NSCLC) have increased significantly. Shan Ci Gu is commonly used as an anticancer drug in traditional Chinese medicine; however, its specific mechanism against NSCLC has not yet been elucidated. Here, the mechanism was clarified through network pharmacology and molecular docking.

Methods: The Traditional Chinese Medicine Systems Pharmacology database was searched for the active ingredients of Shan Ci Gu, and the relevant targets in the Swiss Target Prediction database were obtained according to the structure of the active ingredients. GeneCards were searched for NSCLC-related disease targets. We obtained the cross-target using VENNY to obtain the core targets. The core targets were imported into the Search Tool for the Retrieval of Interacting Genes/Proteins database, and Cytoscape software was used to operate a mesh chart. R software was used to analyze the Gene Ontology biological processes (BPs) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The core targets and active compounds were molecularly docked through Auto-Dock Vina software to predict the detailed molecular mechanism of Shan Ci Gu for NSCLC treatment. We did a simple survival analysis with hub gene to assess the prognosis of NSCLC patients.

Results: Three compounds were screened to obtain 143 target genes and 1,226 targets related to NSCLC, of which 56 genes were related to NSCLC treatment. Shan Ci Gu treatment for NSCLC involved many BPs and acted on main targets including epidermal growth factor receptor (EGFR), ESR1, and SRC through signaling pathways including the endocrine resistance, EGFR tyrosine kinase inhibitor resistance, and ErbB signaling pathways. Shan Ci Gu might be beneficial for treating NSCLC by inhibiting cell proliferation and migration. Molecular docking revealed that the active compounds β-sitosterol, stigmasterol, and 2-methoxy-9,10-dihydrophenanthrene-4,5-diol had good affinity with the core target genes (EGFR, SRC, and ESR1). Core targets included EGFR, SRC, ESR1, ERBB2, MTOR, MCL1, matrix metalloproteinase 2 (MMP2), MMP9, KDR, and JAK2. Key KEGG pathways included endocrine resistance, EGFR tyrosine kinase inhibitor resistance, ErbB signaling, PI3K-Akt signaling, and Rap1 signaling pathways. These core targets and pathways have an inhibitory effect on the proliferation of NSCLC cells.

Conclusion: Shan Ci Gu can treat NSCLC through a multi-target, multi-pathway molecular mechanism and effectively improve NSCLC prognosis. This study could serve as a reference for further mechanistic research on wider application of Shan Ci Gu for NSCLC treatment.
Sirtuin Control of Mitochondrial Dysfunction, Oxidative Stress, and Inflammation in Chagas Disease Models
Authors: Wan Xianxiu , Garg Nisha Jain
Published: June 2021

Trypanosoma cruzi is a digenetic parasite that requires triatomines and mammalian host to complete its life cycle. T. cruzi replication in mammalian host induces immune-mediated cytotoxic proinflammatory reactions and cellular injuries, which are the common source of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during the acute parasitemic phase. Mitochondrial dysfunction of electron transport chain has been proposed as a major source of superoxide release in the chronic phase of infection, which renders myocardium exposed to sustained oxidative stress and contributes to Chagas disease pathology. Sirtuin 1 (SIRT1) is a class III histone deacetylase that acts as a sensor of redox changes and shapes the mitochondrial metabolism and inflammatory response in the host. In this review, we discuss the molecular mechanisms by which SIRT1 can potentially improve mitochondrial function and control oxidative and inflammatory stress in Chagas disease.
Toward Consistent Observational Constraints in Climate Predictions and Projections
Authors: Hegerl Gabriele C. , Ballinger Andrew P. , Booth Ben B. B. , Borchert Leonard F. , Brunner Lukas , Donat Markus G. , Doblas-Reyes Francisco J. , Harris Glen R. , Lowe Jason , Mahmood Rashed , Mignot Juliette , Murphy James M. , Swingedouw Didier , Weisheimer Antje
Published: June 2021

Observations facilitate model evaluation and provide constraints that are relevant to future predictions and projections. Constraints for uninitialized projections are generally based on model performance in simulating climatology and climate change. For initialized predictions, skill scores over the hindcast period provide insight into the relative performance of models, and the value of initialization as compared to projections. Predictions and projections combined can, in principle, provide seamless decadal to multi-decadal climate information. For that, though, the role of observations in skill estimates and constraints needs to be understood in order to use both consistently across the prediction and projection time horizons. This paper discusses the challenges in doing so, illustrated by examples of state-of-the-art methods for predicting and projecting changes in European climate. It discusses constraints across prediction and projection methods, their interpretation, and the metrics that drive them such as process accuracy, accurate trends or high signal-to-noise ratio. We also discuss the potential to combine constraints to arrive at more reliable climate prediction systems from years to decades. To illustrate constraints on projections, we discuss their use in the UK's climate prediction system UKCP18, the case of model performance weights obtained from the Climate model Weighting by Independence and Performance (ClimWIP) method, and the estimated magnitude of the forced signal in observations from detection and attribution. For initialized predictions, skill scores are used to evaluate which models perform well, what might contribute to this performance, and how skill may vary over time. Skill estimates also vary with different phases of climate variability and climatic conditions, and are influenced by the presence of external forcing. This complicates the systematic use of observational constraints. Furthermore, we illustrate that sub-selecting simulations from large ensembles based on reproduction of the observed evolution of climate variations is a good testbed for combining projections and predictions. Finally, the methods described in this paper potentially add value to projections and predictions for users, but must be used with caution.
Challenges and Management of Acute Coronary Syndrome in Cancer Patients
Authors: Costa Isabela Bispo Santos da Silva , Andrade Fernanda Thereza de Almeida , Carter Diego , Seleme Vinicius B. , Costa Maycon Santos , Campos Carlos M. , Hajjar Ludhmila Abrahão
Published: June 2021

Cancer and cardiovascular disease are the leading causes of mortality in the world. The prevalence of cardiovascular risk factors and coronary artery disease in cancer patients is elevated, and it is associated with high mortality. Several mechanisms, such as the proinflammatory and procoagulant states present in cancer patients, may contribute to these scenarios. Oncological therapy can predispose patients to acute thrombosis, accelerated atherosclerosis and coronary spasm. Treatment decisions must be individualized and based on the cancer history and balancing bleeding and thrombosis risks.
Modeling Conditions Appropriate for Wildfire in South East China – A Machine Learning Approach
Authors: Shirazi Zeeshan , Wang Lei , Bondur Valery G.
Published: June 2021

Wildfire is one of the most common natural hazards in the world. Fire risk estimation for the purposes of risk reduction is an important aspect in disaster studies around the world. The aim of this research was to develop a machine learning workflow process for South East China to monitor fire risks over a large region by learning from a grid file database containing a time series of several of the important environmental parameters largely extracted from remote sensing data products, and highlight areas as fire risk or non-fire risk over a couple of weeks in the future. The study employed fire threshold and the transductive PU learning method to identify reliable non-fire/negative training samples from the grid file database using fire/positive training samples, labeled using the MODIS MCD14ML fire location product. Different models were trained for the three natural vegetation land covers, namely evergreen broadleaf forest, mixed forest, and woody savannas in the study area. On the test dataset, the three models exhibited high sensitivity (>80%) by identifying the majority of fires in the test dataset for all land covers. The use of the reliable negatives identified though the fire threshold and PU learning process resulted in low precision and accuracy. During the model verification process, the model for the mixed forest land cover performed the best with 70% of verification fires falling within the classified fire zone. It was found that the better representation of mixed forest in the training samples made this model perform more reliably as compared to others. Improving the individual models constructed for different land covers and combining them can provide fire classification for a larger region. There is room to improve the spatial precision of fire cell classification. Introducing finer scale features that have higher correlation with fire activity and exhibit high spatial variability seems a viable way forward.
The Influence of Particle Concentration on the Formation of Settling-Driven Gravitational Instabilities at the Base of Volcanic Clouds
Authors: Fries Allan , Lemus Jonathan , Jarvis Paul A. , Clarke Amanda B. , Phillips Jeremy C. , Manzella Irene , Bonadonna Costanza
Published: June 2021

Settling-driven gravitational instabilities observed at the base of volcanic ash clouds have the potential to play a substantial role in volcanic ash sedimentation. They originate from a narrow, gravitationally unstable region called a Particle Boundary Layer (PBL) that forms at the lower cloud-atmosphere interface and generates downward-moving ash fingers that enhance the ash sedimentation rate. We use scaled laboratory experiments in combination with particle imaging and Planar Laser Induced Fluorescence (PLIF) techniques to investigate the effect of particle concentration on PBL and finger formation. Results show that, as particles settle across an initial density interface and are incorporated within the dense underlying fluid, the PBL grows below the interface as a narrow region of small excess density. This detaches upon reaching a critical thickness, that scales with (ν2/g′)1/3, where ν is the kinematic viscosity and g′ is the reduced gravity of the PBL, leading to the formation of fingers. During this process, the fluid above and below the interface remains poorly mixed, with only small quantities of the upper fluid phase being injected through fingers. In addition, our measurements confirm previous findings over a wider set of initial conditions that show that both the number of fingers and their velocity increase with particle concentration. We also quantify how the vertical particle mass flux below the particle suspension evolves with time and with the particle concentration. Finally, we identify a dimensionless number that depends on the measurable cloud mass-loading and thickness, which can be used to assess the potential for settling-driven gravitational instabilities to form. Our results suggest that fingers from volcanic clouds characterised by high ash concentrations not only are more likely to develop, but they are also expected to form more quickly and propagate at higher velocities than fingers associated with ash-poor clouds.
Synergistic Influence of Local Climate Zones and Wind Speeds on the Urban Heat Island and Heat Waves in the Megacity of Beijing, China
Authors: Zong Lian , Liu Shuhong , Yang Yuanjian , Ren Guoyu , Yu Miao , Zhang Yanhao , Li Yubin
Published: June 2021

Large-scale modifications to urban underlying surfaces owing to rapid urbanization have led to stronger urban heat island (UHI) effects and more frequent urban heat wave (HW) events. Based on observations of automatic weather stations in Beijing during the summers of 2014–2020, we studied the interaction between HW events and the UHI effect. Results showed that the UHI intensity (UHII) was significantly aggravated (by 0.55°C) during HW periods compared to non-heat wave (NHW) periods. Considering the strong impact of unfavorable weather conditions and altered land use on the urban thermal environment, we evaluated the modulation of HW events and the UHI effect by wind speed and local climatic zones (LCZs). Wind speeds in urban areas were weakened due to the obstruction of dense high-rise buildings, which favored the occurrence of HW events. In detail, 35 HW events occurred over the LCZ1 of a dense high-rise building area under low wind speed conditions, which was much higher than that in other LCZ types and under high wind speed conditions (< 30 HW events). The latent heat flux in rural areas has increased more due to the presence of sufficient water availability and more vegetation, while the increase in heat flux in urban areas is mainly in the form of sensible heat flux, resulting in stronger UHI effect during HW periods. Compared to NHW periods, lower boundary layer and wind speed in the HW events weakened the convective mixing of air, further expanding the temperature gap between urban and rural areas. Note that LCZP type with its high-density vegetation and water bodies in the urban park area generally exhibited, was found to have a mitigating effect on the UHI, whilst at the same time increasing the frequency and duration of HW events during HW periods. Synergies between HWs and the UHI amplify both the spatial and temporal coverage of high-temperature events, which in turn exposes urban residents to additional heat stress and seriously threatens their health. The findings have important implications for HWs and UHII forecasts, as well as for scientific guidance on decision-making to improve the thermal environment and to adjust the energy structure.
Two Cases With an Early Presented Proopiomelanocortin Deficiency—A Long-Term Follow-Up and Systematic Literature Review
Authors: Gregoric Nadan , Groselj Urh , Bratina Natasa , Debeljak Marusa , Zerjav Tansek Mojca , Suput Omladic Jasna , Kovac Jernej , Battelino Tadej , Kotnik Primoz , Avbelj Stefanija Magdalena
Published: June 2021

Proopiomelanocortin (POMC) deficiency is an extremely rare inherited autosomal recessive disorder characterized by severe obesity, adrenal insufficiency, skin hypopigmentation, and red hair. It is caused by pathogenic variants in the POMC gene that codes the proopiomelanocortin polypeptide which is cleaved to several peptides; the most notable ones are adrenocorticotropic hormone (ACTH), alpha- and beta-melanocyte-stimulating hormones (α-MSH and β-MSH); the latter two are crucial in melanogenesis and the energy balance by regulating feeding behavior and energy homeostasis through melanocortin receptor 4 (MC4R). The lack of its regulation leads to polyphagia and early onset severe obesity. A novel MC4R agonist, setmelanotide, has shown promising results regarding weight loss in patients with POMC deficiency. A systematic review on previously published clinical and genetic characteristics of patients with POMC deficiency and additional data obtained from two unrelated patients in our care was performed. A 25-year-old male patient, partly previously reported, was remarkable for childhood developed type 1 diabetes (T1D), transient growth hormone deficiency, and delayed puberty. The second case is a girl with an unusual presentation with central hypothyroidism and normal pigmentation of skin and hair. Of all evaluated cases, only 50% of patients had characteristic red hair, fair skin, and eye phenotype. Central hypothyroidism was reported in 36% of patients; furthermore, scarce adolescent data indicate possible growth axis dysbalance and central hypogonadism. T1D was unexpectedly prevalent in POMC deficiency, reported in 14% of patients, which could be an underestimation. POMC deficiency reveals to be a syndrome with several endocrinological abnormalities, some of which may become apparent with time. Apart from timely diagnosis, careful clinical follow-up of patients through childhood and adolescence for possible additional disease manifestations is warranted.
Prenatal Nicotine Exposure Induces Low Birthweight and Hyperinsulinemia in Male Rats
Authors: Nemoto Takahiro , Ando Hisae , Nagao Mototsugu , Kakinuma Yoshihiko , Sugihara Hitoshi
Published: June 2021

Smoking during pregnancy is one of the causes of low birthweight. Ingestion of nicotine during pregnancy has various metabolic impacts on the fetus and offspring. According to the developmental origins of health and disease theory, low birthweight is a risk factor for developing various non-communicable diseases, including diabetes. We hypothesized that when nicotine-induced low-birthweight rats, when exposed to a high-fat diet (HFD) after growth, are predisposed to glucose intolerance as a result of a mismatch between the eutrophic environment and small body size. Therefore, we investigated whether hyperinsulinemia was caused by exposure of nicotine-induced low-birthweight rats to HFD, including whether this phenomenon exhibited possible sex differences. The average birthweight and body weight at weaning day of offspring from nicotine-administered dams was lower than those of controls. The offspring from nicotine-administered dams did not show rapid fat accumulation after exposure to HFD, and weight and body fat ratio of these animals did not differ from those of the controls. Blood glucose levels did not differ between the groups, but insulin levels increased only in male HFD-exposed offspring from nicotine-administered dams. Similarly, only in HFD-exposed male from nicotine-administered dams showed decreases in the insulin receptor expression in the liver. We conclude that male rats subjected to prenatal nicotine exposure develop hyperinsulinemia when exposed to HFD after growth. Our results suggest that decreased expression of insulin receptors in the liver may be involved in the mechanism underlying hyperinsulinemia in low-birthweight offspring, a phenomenon that appeared to exhibit a sex-specific bias.
Coupled Modeling and Simulation of Phase Transformation in Zircaloy-4 Fuel Cladding Under Loss-of-Coolant Accident Conditions
Authors: Lu Wenjun , Qian Libo , Zhou Wenzhong
Published: June 2021

Under loss-of-coolant conditions, the temperature on fuel cladding will increase rapidly (up to 1000–1500 K), which will not only cause a dramatic oxidation reaction of Zircaloy-4 and an increase in hydrogen concentration but also cause an allotropic phase transformation of Zircaloy-4 from hexagonal (α-pahse) to cubic (β-phase) crystal structure. As we all know, thermophysical properties have a close relationship with the microstructure of the material. Moreover, because of an important influence of the phase transformation on the creep resistance and the ductility of the fuel rod, studying the crystallographic phase transformation kinetics is pivotal for evaluating properties for fuel rod completeness. We coupled the phase transformation model together with the existing physical models for reactor fuel, gap, cladding, and coolant, based on the finite element analysis and simulation software COMSOL Multiphysics. The critical parameter for this transformation is the evolution of the volume fraction of the favored phase described by a function of time and temperature. Hence, we choose two different volume fractions (0 and 10%) of BeO for UO2-BeO enhanced thermal conductivity nuclear fuel and zircaloy cladding as objects of this study. In order to simulate loss-of-coolant accident conditions, five relevant parameters are studied, including the gap size between fuel and cladding, the temperature at the extremities of the fuel element, the coefficient of heat transfer, the linear power rate, and the coolant temperature, to see their influence on the behavior of phase transformation under non-isothermal conditions. The results show that the addition of 10vol%BeO in the UO2 fuel decreased the phase transformation effect a lot, and no significant phase transformation was observed in Zircaloy-4 cladding with UO2-BeO enhanced thermal conductivity nuclear fuel during existing loss-of-coolant accident conditions.
Climate Change Can Drive a Significant Loss of Suitable Habitat for Polylepis quadrijuga, a Treeline Species in the Sky Islands of the Northern Andes
Authors: Caballero-Villalobos Lina , Fajardo-Gutiérrez Francisco , Calbi Mariasole , Silva-Arias Gustavo A.
Published: June 2021

It is predicted that climate change will strongly affect plant distributions in high elevation “sky islands” of tropical Andes. Polylepis forests are a dominant element of the treeline throughout the Andes Cordillera in South America. However, little is known about the climatic factors underlying the current distribution of Polylepis trees and the possible effect of global climate change. The species Polylepis quadrijuga is endemic to the Colombian Eastern Cordillera, where it plays a fundamental ecological role in high-altitude páramo-forest ecotones. We sought to evaluate the potential distribution of P. quadrijuga under future climate change scenarios using ensemble modeling approaches. We conducted a comprehensive assessment of future climatic projections deriving from 12 different general circulation models (GCMs), four Representative Concentration Pathways (R) emissions scenarios, and two different time frames (2041–2060 and 2061–2080). Additionally, based on the future projections, we evaluate the effectiveness of the National System of Protected Natural Areas of Colombia (SINAP) and Páramo Complexes of Colombia (PCC) in protecting P. quadrijuga woodlands. Here, we compiled a comprehensive set of observations of P. quadrijuga and study them in connection with climatic and topographic variables to identify environmental predictors of the species distribution, possible habitat differentiation throughout the geographic distribution of the species, and predict the effect of different climate change scenarios on the future distribution of P. quadrijuga. Our results predict a dramatic loss of suitable habitat due to climate change on this key tropical Andean treeline species. The ensemble Habitat Suitability Modeling (HSM) shows differences in suitable scores among north and south regions of the species distribution consistent with differences in topographic features throughout the available habitat of P. quadrijuga. Future projections of the HSM predicted the Páramo complex “Sumapaz-Cruz Verde” as a major area for the long-term conservation of P. quadrijuga because it provides a wide range of suitable habitats for the different evaluated climate change scenarios. We provide the first set of priority areas to perform both in situ and ex situ conservation efforts based on suitable habitat projections.
Ionizing Radiation Curtails Immunosuppressive Effects From Cancer-Associated Fibroblasts on Dendritic Cells
Authors: Berzaghi Rodrigo , Tornaas Stian , Lode Kristin , Hellevik Turid , Martinez-Zubiaurre Inigo
Published: June 2021

Cancer-associated fibroblasts (CAFs) participate actively in tumor development and affect treatment responses, by among other mechanisms, promoting an immunosuppressive tumor microenvironment. In contrast to normal fibroblasts, reactive CAFs secrete a myriad of immunomodulatory soluble factors at high levels, i.e. growth factors, cytokines, and chemokines, which directly influence tumor immunity and inflammation. CAFs have been identified as important players in tumor radioresistance. However, knowledge on the immunomodulatory functions of CAFs during/after radiotherapy is still lacking. In this study, we investigated the effects of ionizing radiation on CAF-mediated regulation of dendritic cells (DCs). CAFs were obtained from freshly operated lung cancer tissues, while DCs were procured from peripheral blood of healthy donors. Experimental settings comprised both co-cultures and incubations with conditioned medium from control and irradiated CAFs. Functional assays to study DC differentiation/activation consisted on cytokine release, expression of cell-surface markers, antigen uptake, migration rates, T cell priming, and DC-signaling analysis. We demonstrate that CAFs induce a tolerogenic phenotype in DCs by promoting down-regulation of: i) signature DC markers (CD14, CD1a, CD209); ii) activation markers (CD80, CD86, CD40, and HLA-DR) and iii) functional properties (migration, antigen uptake, and CD4+ T cell priming). Notably, some of these effects were lost in conditioned medium from CAFs irradiated at fractionated medium-dose regimens (3x6 Gy). However, the expression of relevant CAF-derived regulatory agents like thymic stromal lymphopoietin (TSLP) or tryptophan 2,3-dioxygenase (TDO2) was unchanged upon irradiation. This study demonstrates that CAFs interfere with DC immune functions and unveil that certain radiation regimens may reverse CAF-mediated immunosuppressive effects.
Blood Cardioplegia Induction, Perfusion Storage and Graft Dysfunction in Cardiac Xenotransplantation
Authors: Goerlich Corbin E. , Griffith Bartley , Singh Avneesh K. , Abdullah Mohamed , Singireddy Shreya , Kolesnik Irina , Lewis Billeta , Sentz Faith , Tatarov Ivan , Hershfeld Alena , Zhang Tianshu , Strauss Erik , Odonkor Patrick , Williams Brittney , Tabatabai Ali , Bhutta Adnan , Ayares David , Kaczorowski David J. , Mohiuddin Muhammad M.
Published: June 2021

Background

Perioperative cardiac xenograft dysfunction (PCXD) describes a rapidly developing loss of cardiac function after xenotransplantation. PCXD occurs despite genetic modifications to increase compatibility of the heart. We report on the incidence of PCXD using static preservation in ice slush following crystalloid or blood-based cardioplegia versus continuous cold perfusion with XVIVO©heart solution (XHS) based cardioplegia.

Methods

Baboons were weight matched to genetically engineered swine heart donors. Cardioplegia volume was 30 cc/kg by donor weight, with del Nido cardioplegia and the addition of 25% by volume of donor whole blood. Continuous perfusion was performed using an XVIVO©Perfusion system with XHS to which baboon RBCs were added.

Results

PCXD was observed in 5/8 that were preserved with crystalloid cardioplegia followed by traditional cold, static storage on ice. By comparison, when blood cardioplegia was used followed by cold, static storage, PCXD occurred in 1/3 hearts and only in 1/5 hearts that were induced with XHS blood cardioplegia followed by continuous perfusion. Survival averaged 17 hours in those with traditional preservation and storage, followed by 11.47 days and 15.03 days using blood cardioplegia and XHS+continuous preservation, respectively. Traditional preservation resulted in more inotropic support and higher average peak serum lactate 14.3±1.7 mmol/L compared to blood cardioplegia 3.6±3.0 mmol/L and continuous perfusion 3.5±1.5 mmol/L.

Conclusion

Blood cardioplegia induction, alone or followed by XHS perfusion storage, reduced the incidence of PCXD and improved graft function and survival, relative to traditional crystalloid cardioplegia-slush storage alone.
Mucosal and Systemic Immune Responses to Salmon Gill Poxvirus Infection in Atlantic Salmon Are Modulated Upon Hydrocortisone Injection
Authors: Amundsen Marit M. , Tartor Haitham , Andersen Kathrine , Sveinsson Karoline , Thoen Even , Gjessing Mona C. , Dahle Maria K.
Published: June 2021

Salmon Gill Poxvirus Disease (SGPVD) has emerged as a cause of acute mortality in Atlantic salmon (Salmo salar L.) presmolts in Norwegian aquaculture. The clinical phase of the disease is associated with apoptotic cell death in the gill epithelium causing acute respiratory distress, followed by proliferative changes in the regenerating gill in the period after the disease outbreak. In an experimental SGPV challenge trial published in 2020, acute disease was only seen in fish injected with hydrocortisone 24 h prior to infection. SGPV-mediated mortality in the hydrocortisone-injected group was associated with more extensive gill pathology and higher SGPV levels compared to the group infected with SGPV only. In this study based on the same trial, SGPV gene expression and the innate and adaptive antiviral immune response was monitored in gills and spleen in the presence and absence of hydrocortisone. Whereas most SGPV genes were induced from day 3 along with the interferon-regulated innate immune response in gills, the putative SGPV virulence genes of the B22R family were expressed already one day after SGPV exposure, indicating a potential role as early markers of SGPV infection. In gills of the hydrocortisone-injected fish infected with SGPV, MX expression was delayed until day 10, and then expression skyrocketed along with the viral peak, gill pathology and mortality occurring from day 14. A similar expression pattern was observed for Interferon gamma (IFNγ) and granzyme A (GzmA) in the gills, indicating a role of acute cytotoxic cell activity in SGPVD. Duplex in situ hybridization demonstrated effects of hydrocortisone on the number and localization of GzmA-containing cells, and colocalization with SGPV infected cells in the gill. SGPV was generally not detected in spleen, and gill infection did not induce any corresponding systemic immune activity in the absence of stress hormone injection. However, in fish injected with hydrocortisone, IFNγ and GzmA gene expression was induced in spleen in the days prior to acute mortality. These data indicate that suppressed mucosal immune response in the gills and the late triggered systemic immune response in the spleen following hormonal stress induction may be the key to the onset of clinical SGPVD.
Obesity Challenge Drives Distinct Maternal Immune Response Changes in Normal Pregnant and Abortion-Prone Mouse Models
Authors: Li Yanhong , Chen Jiajia , Lin Yikong , Xu Ling , Sang Yifei , Li Dajin , Du Meirong
Published: June 2021

Obesity is prevalent among women of reproductive age and is associated with increased risk of developing multiple pregnancy disorders. Pregnancy must induce immune tolerance to avoid fetal rejection, while obesity can cause chronic inflammation through activating the immune system. Impaired maternal immuno-tolerance leads to pregnancy failure, such as recurrent spontaneous abortion (RSA), one of the most common complications during early pregnancy. How does maternal immune response change under obesity stress in normal pregnancy and RSA? In turn, is obesity affected by different gestational statuses? Limited information is presently available now. Our study investigated pregnancy outcomes and maternal immune responses in two murine models (normal pregnancy and spontaneous abortion models) after obesity challenge with a high-fat diet (HFD). Abortion-prone mice fed HFD had significantly higher weight gains during pregnancy than normal pregnant mice with HFD feeding. Nonetheless, the embryo implantation and resorption rates were comparable between HFD and normal chow diet (NCD)-fed mice in each model. Evaluation of immune cell subsets showed HFD-induced obesity drove the upregulation of activated NK cell-activating receptor (NKp46)+NK cells and pro-inflammatory macrophages (MHCIIhighMφ) as well as CD4+and CD8+T cells in the normal pregnancy group. However, in the abortion-prone group, relative more immature NK cells with decreased activity phenotypes were found in obese mice. Moreover, there were increased DCreg (CD11bhighDC) cells and decreased CD4+and CD8+T cells detected in the HFD abortion-prone mice relative to those fed the NCD diet. Our findings reveal how pregnancy obesity and maternal immune regulation are mutually influenced. It is worth noting that the abortion-prone model where active maternal immune status was intensified by obesity, in turn stimulated an overcompensation response, leading to an over-tolerized immune status, and predisposing to potential risks of perinatal complications.
Recent Semen Exposure Impacts the Cytokine Response and Bacterial Vaginosis in Women
Authors: Mngomezulu Khanyisile , Mzobe Gugulethu F. , Mtshali Andile , Osman Farzana , Liebenberg Lenine J. P. , Garrett Nigel , Singh Ravesh , Rompalo Anne , Mindel Adrian , Karim Salim S. Abdool , Karim Quarraisha Abdool , Baxter Cheryl , Ngcapu Sinaye
Published: June 2021

Background

The presence of semen in the vagina from unprotected sex may influence the immune and microbial environment of the female genital tract. Inflammatory cytokine concentrations and BV-associated bacteria in female genital secretions may influence HIV risk, although the effect of recent sexual intercourse on incident BV and the cytokine milieu of cervicovaginal secretions has rarely been measured in previous studies. Here, we investigated the extent to which partner semen impacts the cytokine response and incident BV.

Methods

At baseline, we assessed the recency of semen exposure in menstrual cup supernatants by quantifying prostate specific antigen (PSA) levels using ELISA in 248 HIV-uninfected women at high risk for HIV infection. Luminex was used to measure 48 cytokines in menstrual cup supernatants and vaginal swabs to diagnose BV by Nugent score. Point-of-care screening for Chlamydia trachomatis and Neisseria gonorrhoeae was conducted using GeneXpert while OSOM was used for Trichomonas vaginalis detection. Multivariable models, adjusted for age, sexually transmitted infections, BV, current contraception use and condom use, were used to assess the impact of semen exposure on biomarkers of inflammation and BV.

Results

Presence of PSA, indicating recent semen exposure within 48 hours prior to sampling, was observed in menstrual cup supernatants of 17% (43/248) of women. Of these women, 70% (30/43) had self-reported condom use at their last sex act and 84% (36/43) had BV (Nugent score >7). PSA presence was significantly associated with prevalent BV (Relative Risk (RR), 2.609; 95% Confidence Interval (CI), 1.104 - 6.165; p = 0.029). Furthermore, women with detectable PSA had high median concentrations of macrophage inflammatory protein- beta (MIP-1α, p=0.047) and low median concentration of the stem cell growth factor beta (SCGF-β, p=0.038) compared to those without PSA.

Conclusion

A degree of discordance between self-reports of consistent condom use and PSA positivity was observed. There was also evidence of a relationship between recent semen exposure, BV prevalence and altered cytokine concentrations. These findings suggest that PSA, as a semen biomarker, should be taken into consideration when investigating biological markers in the female genital tract and self-reported condom use in studies on reproductive and sexual health.
Applications of Single-Cell Omics in Tumor Immunology
Authors: Liu Junwei , Qu Saisi , Zhang Tongtong , Gao Yufei , Shi Hongyu , Song Kaichen , Chen Wei , Yin Weiwei
Published: June 2021

The tumor microenvironment (TME) is an ecosystem that contains various cell types, including cancer cells, immune cells, stromal cells, and many others. In the TME, cancer cells aggressively proliferate, evolve, transmigrate to the circulation system and other organs, and frequently communicate with adjacent immune cells to suppress local tumor immunity. It is essential to delineate this ecosystem’s complex cellular compositions and their dynamic intercellular interactions to understand cancer biology and tumor immunology and to benefit tumor immunotherapy. But technically, this is extremely challenging due to the high complexities of the TME. The rapid developments of single-cell techniques provide us powerful means to systemically profile the multiple omics status of the TME at a single-cell resolution, shedding light on the pathogenic mechanisms of cancers and dysfunctions of tumor immunity in an unprecedently resolution. Furthermore, more advanced techniques have been developed to simultaneously characterize multi-omics and even spatial information at the single-cell level, helping us reveal the phenotypes and functionalities of disease-specific cell populations more comprehensively. Meanwhile, the connections between single-cell data and clinical characteristics are also intensively interrogated to achieve better clinical diagnosis and prognosis. In this review, we summarize recent progress in single-cell techniques, discuss their technical advantages, limitations, and applications, particularly in tumor biology and immunology, aiming to promote the research of cancer pathogenesis, clinically relevant cancer diagnosis, prognosis, and immunotherapy design with the help of single-cell techniques.
Change of Hemoglobin Levels in the Early Post-cardiac Arrest Phase Is Associated With Outcome
Authors: Schriefl Christoph , Schoergenhofer Christian , Ettl Florian , Poppe Michael , Clodi Christian , Mueller Matthias , Grafeneder Juergen , Jilma Bernd , Magnet Ingrid Anna Maria , Buchtele Nina , Boegl Magdalena Sophie , Holzer Michael , Sterz Fritz , Schwameis Michael
Published: June 2021

Background: The post-cardiac arrest (CA) phase is characterized by high fluid requirements, endothelial activation and increased vascular permeability. Erythrocytes are large cells and may not leave circulation despite massive capillary leak. We hypothesized that dynamic changes in hemoglobin concentrations may reflect the degree of vascular permeability and may be associated with neurologic function after CA.

Methods: We included patients ≥18 years, who suffered a non-traumatic CA between 2013 and 2018 from the prospective Vienna Clinical Cardiac Arrest Registry. Patients without return of spontaneous circulation (ROSC), with extracorporeal life support, with any form of bleeding, undergoing surgery, receiving transfusions, without targeted temperature management or with incomplete datasets for multivariable analysis were excluded. The primary outcome was neurologic function at day 30 assessed by the Cerebral Performance Category scale. Differences of hemoglobin concentrations at admission and 12 h after ROSC were calculated and associations with neurologic function were investigated by uni- and multivariable logistic regression.

Results: Two hundred and seventy-five patients were eligible for analysis of which 143 (52%) had poor neurologic function. For every g/dl increase in hemoglobin from admission to 12 h the odds of poor neurologic function increased by 26% (crude OR 1.26, 1.07–1.49, p = 0.006). The effect remained unchanged after adjustment for fluid balance and traditional prognostication markers (adjusted OR 1.27, 1.05–1.54, p = 0.014).

Conclusion: Increasing hemoglobin levels in spite of a positive fluid balance may serve as a surrogate parameter of vascular permeability and are associated with poor neurologic function in the early post-cardiac arrest period.
Urinary Extracellular Vesicles for Renal Tubular Transporters Expression in Patients With Gitelman Syndrome
Authors: Sung Chih-Chien , Chen Min-Hsiu , Lin Yi-Chang , Lin Yu-Chun , Lin Yi-Jia , Yang Sung-Sen , Lin Shih-Hua
Published: June 2021

Background: The utility of urinary extracellular vesicles (uEVs) to faithfully represent the changes of renal tubular protein expression remains unclear. We aimed to evaluate renal tubular sodium (Na+) or potassium (K+) associated transporters expression from uEVs and kidney tissues in patients with Gitelman syndrome (GS) caused by inactivating mutations in SLC12A3.

Methods: uEVs were isolated by ultracentrifugation from 10 genetically-confirmed GS patients. Membrane transporters including Na+-hydrogen exchanger 3 (NHE3), Na+/K+/2Cl− cotransporter (NKCC2), NaCl cotransporter (NCC), phosphorylated NCC (p-NCC), epithelial Na+ channel β (ENaCβ), pendrin, renal outer medullary K1 channel (ROMK), and large-conductance, voltage-activated and Ca2+-sensitive K+ channel (Maxi-K) were examined by immunoblotting of uEVs and immunofluorescence of biopsied kidney tissues. Healthy and disease (bulimic patients) controls were also enrolled.

Results: Characterization of uEVs was confirmed by nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting. Compared with healthy controls, uEVs from GS patients showed NCC and p-NCC abundance were markedly attenuated but NHE3, ENaCβ, and pendrin abundance significantly increased. ROMK and Maxi-K abundance were also significantly accentuated. Immunofluorescence of the representative kidney tissues from GS patients also demonstrated the similar findings to uEVs. uEVs from bulimic patients showed an increased abundance of NCC and p-NCC as well as NHE3, NKCC2, ENaCβ, pendrin, ROMK and Maxi-K, akin to that in immunofluorescence of their kidney tissues.

Conclusion: uEVs could be a non-invasive tool to diagnose and evaluate renal tubular transporter adaptation in patients with GS and may be applied to other renal tubular diseases.