bluuebunny/crossref_metadata_2025 huggingface dataset:
TP53 Mutational Status-Based Genomic Signature for Prognosis and Predicting Therapeutic Response in Pancreatic Cancer
Authors: Zhang Feng , Zhong Wenhui , Li Honghao , Huang Kaijun , Yu Min , Liu Yubin
Published: May 2021

TP53 mutation is a critical driver mutation that affects the carcinogenesis and prognosis of patients with pancreatic cancer (PC). Currently, there is no driver mutation-derived signature based on TP53 mutational status for prognosis and predicting therapeutic response in PC. In the present study, we characterized the TP53 mutational phenotypes in multiple patient cohorts and developed a prognostic TP53-associated signature based on differentially expressed genes between PC samples with mutated TP53 and wild-type TP53. Comprehensive investigations were carried out in prognostic stratification, genetic variation, immune cell infiltration, and efficacy prediction of chemotherapy and targeted therapy. We found that TP53 mutation commonly occurred as a survival-related driver mutation in PC. In total, 1,154 differentially expressed genes were found between two distinct TP53 mutational phenotypes. A five-gene TP53-associated signature was constructed in The Cancer Genome Atlas (TCGA) cohort by least absolute shrinkage and selection operator (LASSO)–Cox analysis and proven to be a robust prognostic predictor, which performed well in three independent Gene Expression Omnibus (GEO) validating cohorts. Remarkably, patients in the low-risk group were characterized with decreased tumor mutation burden and activity of immunity, with favorable prognosis. Higher fractions of macrophages M0 and impaired CD8 + T cells were observed in patients in the high-risk group, suggesting immunosuppression with poor survival. Patients in the high-risk group also demonstrated enhanced response to specific chemotherapeutic agents, including gemcitabine and paclitaxel. Several targeted inhibitors, like histamine receptor inhibitor, were screened out as promising drugs for PC treatment. Collectively, the TP53-associated signature is a novel prognostic biomarker and predictive indicator of PC. The signature could contribute to optimizing prognostic stratification and guide effective PC treatments.
Force-Induced Autophagy in Periodontal Ligament Stem Cells Modulates M1 Macrophage Polarization via AKT Signaling
Authors: Jiang Nan , He Danqing , Ma Yushi , Su Junxiang , Wu Xiaowen , Cui Shengjie , Li Zixin , Zhou Yanheng , Yu Huajie , Liu Yan
Published: May 2021

Autophagy, a lysosomal degradation pathway, serves as a protective cellular mechanism in maintaining cell and tissue homeostasis under mechanical stimulation. As the mechanosensitive cells, periodontal ligament stem cells (PDLSCs) play an important role in the force-induced inflammatory bone remodeling and tooth movement process. However, whether and how autophagy in PDLSCs influences the inflammatory bone remodeling process under mechanical force stimuli is still unknown. In this study, we found that mechanical force stimuli increased the expression of the autophagy protein LC3, the number of M1 macrophages and osteoclasts, as well as the ratio of M1/M2 macrophages in the compression side of the periodontal ligament in vivo. These biological changes induced by mechanical force were repressed by the application of an autophagy inhibitor 3-methyladenine. Moreover, autophagy was activated in the force-loaded PDLSCs, and force-stimulated PDLSC autophagy further induced M1 macrophage polarization in vitro. The macrophage polarization could be partially blocked by the administration of autophagy inhibitor 3-methyladenine or enhanced by the administration of autophagy activator rapamycin in PDLSCs. Mechanistically, force-induced PDLSC autophagy promoted M1 macrophage polarization via the inhibition of the AKT signaling pathway. These data suggest a novel mechanism that force-stimulated PDLSC autophagy steers macrophages into the M1 phenotype via the AKT signaling pathway, which contributes to the inflammatory bone remodeling and tooth movement process.
Pathological Crosstalk Between Oxidized LDL and ER Stress in Human Diseases: A Comprehensive Review
Authors: Varghese Divya Saro , Ali Bassam R.
Published: May 2021

The oxidative modification of the major cholesterol carrying lipoprotein, oxLDL, is a biomarker as well as a pathological factor in cardiovascular diseases (CVD), type 2 diabetes mellitus (T2DM), obesity and other metabolic diseases. Perturbed cellular homeostasis due to physiological, pathological and pharmacological factors hinder the proper functioning of the endoplasmic reticulum (ER), which is the major hub for protein folding and processing, lipid biosynthesis and calcium storage, thereby leading to ER stress. The cellular response to ER stress is marked by a defensive mechanism called unfolded protein response (UPR), wherein the cell adapts strategies that favor survival. Under conditions of excessive ER stress, when the survival mechanisms fail to restore balance, UPR switches to apoptosis and eliminates the defective cells. ER stress is a major hallmark in metabolic syndromes such as diabetes, non-alcoholic fatty liver disease (NAFLD), neurological and cardiovascular diseases. Though the pathological link between oxLDL and ER stress in cardiovascular diseases is well-documented, its involvement in other diseases is still largely unexplored. This review provides a deep insight into the common mechanisms in the pathogenicity of diseases involving oxLDL and ER stress as key players. In addition, the potential therapeutic intervention of the targets implicated in the pathogenic processes are also explored.
Oncostatin M Maintains Naïve Pluripotency of mESCs by Tetraploid Embryo Complementation (TEC) Assay
Authors: Ye Xiaoying , Tian Chenglei , Liu Linlin , Feng Guofeng , Jin Kairang , Wang Haiying , Chen Jiyu , Liu Lin
Published: May 2021

It has been well established that leukemia inhibitory factor (LIF) is essential for maintaining naïve pluripotency of embryonic stem cells (ESCs). Oncostatin M (OSM) is a member of the IL-6 family of cytokines which share gp130 as a receptor subunit, and the OSM-gp130 complex can recruit either LIF receptor β or OSM receptor β. Here we show that OSM can completely replace LIF to maintain naïve pluripotency of ESCs. Mouse ESCs (mESCs) cultured in the presence of LIF or OSM not only express pluripotency genes at similar levels but also exhibit the same developmental pluripotency as evidenced by the generation of germline competent chimeras, supporting previous findings. Moreover, we demonstrate by tetraploid embryo complementation assay, the most stringent functional test of authentic pluripotency that mESCs cultured in OSM produce viable all-ESC pups. Furthermore, telomere length and telomerase activity, which are also crucial for unlimited self-renewal and genomic stability of mESCs, do not differ in mESCs cultured under OSM or LIF. The transcriptome of mESCs cultured in OSM overall is very similar to that of LIF, and OSM activates Stat3 signaling pathway, like LIF. Additionally, OSM upregulates pentose and glucuronate interconversion, ascorbate and aldarate metabolism, and steroid and retinol metabolic pathways. Although the significance of these pathways remains to be determined, our data shows that OSM can maintain naïve pluripotent stem cells in the absence of LIF.
Conquering the Tyranny of Number With Digital Microfluidics
Authors: Yang Ya-Tang , Ho Tsung-Yi
Published: May 2021

The development of large-scale integration based on soft lithography has ushered a new revolution in microfluidics. This technology, however, relies inherently on pneumatic control of micromechanical valves that require air pressure to operate, while digital microfluidics uses a purely electrical signal on an electrode for droplet manipulation. In this article, we discuss the prospect and current challenges of digital microfluidics to solve the problem of the tyranny of numbers in arbitrary fluidic manipulation. We distill the fundamental physics governing electrowetting and their implications for specifications of the control electronics. We survey existing control electronics in digital microfluidics and detail the improvements needed to realize a low-power, programmable digital microfluidic system. Such an instrument would attract wide interest in both professional and non-professional (hobbyist) communities.
The Controlled Synthesis of Birnessite Nanoflowers via H2O2 Reducing KMnO4 For Efficient Adsorption and Photooxidation Activity
Authors: Li Yang , Jiang Guanjie , Ouyang Nanqi , Qin Zhangjie , Lan Shuai , Zhang Qin
Published: May 2021

Birnessite nanoflowers composed of layers have been proven to be the strongest adsorbent and oxidant in the surface environment. However, the current synthesis methods of birnessite nanoflowers are suffering from long reaction time and high reaction temperature. Based on these, this paper explores a new method for the rapid and controlled synthesis of layered manganese oxides. The method relies on the molar ratios of KMnO4 and H2O2 redox reacting species to drive the production of birnessite nanoflowers under acidic conditions. The molar ratios of KMnO4 and H2O2 are the key to the crystal structure of the as-prepared. It was found that when the molar ratios of KMnO4 and H2O2 is from 1:1.25 to 1:1.90, the sample is birnessite nanoflowers, and when the ratio is increased to 1:2.0, the sample is a mixture of birnessite nanoflowers and feitknechtite nanoplates. Among the as-prepared samples, BF-1.85 (molar ratios of KMnO4 and H2O2 is 1:1.85) shows the highest capacity for Pb2+ adsorption (2,955 mmol/kg) and greatest degradation efficiency of phenol and TOC. The method proposed herein is economical and controllable, and it yields products with high efficiency for the elimination of inorganic and organic pollutants.
Extracellular Nucleic Acids Present in the Candida albicans Biofilm Trigger the Release of Neutrophil Extracellular Traps
Authors: Smolarz Magdalena , Zawrotniak Marcin , Satala Dorota , Rapala-Kozik Maria
Published: May 2021

Neutrophils, the first line of the host’s defense, use a variety of antimicrobial mechanisms to fight invading pathogens. One of the most crucial is the production of neutrophil extracellular traps (NETs) in the process called NETosis. The unique structure of NETs effectively inhibits the spread of pathogens and ensures their exposure to a high concentration of NET-embedded antimicrobial compounds. NETosis strategy is often used by the host to defend against fungal infection caused by Candida albicans. In immunocompromised patients, this microorganism is responsible for developing systemic fungal infections (candidiasis). This is correlated with the use of a vast array of virulence factors, leading to the acquisition of specific resistance to host defense factors and available drug therapies. One of the most important features favoring the development of drug resistance is a C. albicans ability to form biofilms that protect fungal cells mainly through the production of an extracellular matrix (ECM). Among the main ECM-building macromolecules extracellular nucleic acids have been identified and their role is probably associated with the stbilization of the biofilm structure. The complex interactions of immune cells with the thick ECM layer, comprising the first line of contact between these cells and the biofilm structure, are still poorly understood. Therefore, the current studies aimed to assess the release of extracellular nucleic acids by C. albicans strains at different stages of biofilm formation, and to determine the role of these molecules in triggering the NETosis. We showed for the first time that fungal nucleic acids, purified directly from mature C. albicans biofilm structure or obtained from the whole fungal cells, have the potential to induce NET release in vitro. In this study, we considered the involvement of TLR8 and TLR9 in NETosis activation. We showed that DNA and RNA molecules initiated the production of reactive oxygen species (ROS) by activation of the NADPH oxidase complex, essential for ROS-dependent NETosis. Furthermore, analysis of the cell migration showed that the nucleic acids located in the extracellular space surrounding the biofilm may be also effective chemotactic factors, driving the dynamic migration of human neutrophils to the site of ongoing fungal infection.
Circ_0068087 Silencing Ameliorates Oxidized Low-Density Lipoprotein-Induced Dysfunction in Vascular Endothelial Cells Depending on miR-186-5p-Mediated Regulation of Roundabout Guidance Receptor 1
Authors: Li Shuanghong , Huang Tao , Qin Limin , Yin Luchang
Published: May 2021

Background: Circular RNAs (circRNAs) are endogenous non-coding RNAs involved in the progression of atherosclerosis (AS). We investigated the role of circ_0068087 in AS progression and its associated mechanism.

Methods: The 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay, flow cytometry, and enzyme-linked immunosorbent assay (ELISA) were performed to analyze the viability, apoptosis, and inflammatory response of HUVECs, respectively. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and the Western blot assay were performed to measure the expression of RNA and protein. Cell oxidative stress was analyzed using commercial kits. The dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were conducted to verify the interaction between microRNA-186-5p (miR-186-5p) and circ_0068087 or roundabout guidance receptor 1 (ROBO1).

Results: Oxidized low-density lipoprotein (ox-LDL) exposure upregulated the circ_0068087 level in HUVECs. ox-LDL-induced dysfunction in HUVECs was largely attenuated by the silence of circ_0068087. Circ_0068087 negatively regulated the miR-186-5p level by interacting with it in HUVECs. Circ_0068087 knockdown restrained ox-LDL-induced injury in HUVECs partly by upregulating miR-186-5p. ROBO1 was a downstream target of miR-186-5p in HUVECs. Circ_0068087 positively regulated ROBO1 expression by sponging miR-186-5p in HUVECs. MiR-186-5p overexpression exerted a protective role in ox-LDL-induced HUVECs partly by downregulating ROBO1.

Conclusion: Circ_0068087 interference alleviated ox-LDL-induced dysfunction in HUVECs partly by reducing ROBO1 expression via upregulating miR-186-5p.
Sexual Dimorphism of the Heart: Genetics, Epigenetics, and Development
Authors: Deegan Daniel F. , Nigam Priya , Engel Nora
Published: May 2021

The democratization of genomic technologies has revealed profound sex biases in expression patterns in every adult tissue, even in organs with no conspicuous differences, such as the heart. With the increasing awareness of the disparities in cardiac pathophysiology between males and females, there are exciting opportunities to explore how sex differences in the heart are established developmentally. Although sexual dimorphism is traditionally attributed to hormonal influence, expression and epigenetic sex biases observed in early cardiac development can only be accounted for by the difference in sex chromosome composition, i.e., XX in females and XY in males. In fact, genes linked to the X and Y chromosomes, many of which encode regulatory factors, are expressed in cardiac progenitor cells and at every subsequent developmental stage. The effect of the sex chromosome composition may explain why many congenital heart defects originating before gonad formation exhibit sex biases in presentation, mortality, and morbidity. Some transcriptional and epigenetic sex biases established soon after fertilization persist in cardiac lineages, suggesting that early epigenetic events are perpetuated beyond early embryogenesis. Importantly, when sex hormones begin to circulate, they encounter a cardiac genome that is already functionally distinct between the sexes. Although there is a wealth of knowledge on the effects of sex hormones on cardiac function, we propose that sex chromosome-linked genes and their downstream targets also contribute to the differences between male and female hearts. Moreover, identifying how hormones influence sex chromosome effects, whether antagonistically or synergistically, will enhance our understanding of how sex disparities are established. We also explore the possibility that sexual dimorphism of the developing heart predicts sex-specific responses to environmental signals and foreshadows sex-biased health-related outcomes after birth.
The Leukocyte Subtype Counts and Ratios Can Effectively Predict the Risk of Arterial Stiffness Assessed by Cardio-Ankle Vascular Index: A Retrospective Study
Authors: Wang Yaoling , Wang Ruiyun , Bai Lijuan , Liu Yun , Liu Lihua , He Linfeng , Qi Benling
Published: May 2021

Background: Arterial stiffness was the pathological basis and risk factor of cardiovascular diseases, with chronic inflammation as the core characteristic. We aimed to analyze the association between the arterial stiffness measured by cardio-ankle vascular index (CAVI) and indicators reflecting the inflammation degree, such as count of leukocyte subtypes, platelet, and monocyte-to-lymphocyte ratio (MLR), etc.

Methods: The data of inpatients from November 2018 to November 2019 and from December 2019 to September 2020 were continuously collected as the training set (1,089 cases) and the validation set (700 cases), respectively. A retrospective analysis of gender subgroups was performed in the training set. The association between inflammatory indicators and CAVI or arterial stiffness by simple linear regression, multiple linear regression, and logistic regression was analyzed. The effectiveness of the inflammation indicators and the CAVI decision models to identify arterial stiffness by receiver operating curve (ROC) in the training and validation set was evaluated.

Results: The effect weights of MLR affecting the CAVI were 12.87% in men. MLR was the highest risk factor for arterial stiffness, with the odds ratio (95% confidence interval) of 8.95 (5.04–184.79) in men after adjusting the covariates. A cutpoint MLR of 0.19 had 70% accuracy for identifying arterial stiffness in all participants. The areas under the ROC curve of the CAVI decision models for arterial stiffness were >0.80 in the training set and validation set.

Conclusions: The MLR might be a high-risk factor for arterial stiffness and could be considered as a potential indicator to predict arterial stiffness.
Molecular and Mechanical Mechanisms of Calcification Pathology Induced by Bicuspid Aortic Valve Abnormalities
Authors: Kazik Hail B. , Kandail Harkamaljot S. , LaDisa John F. , Lincoln Joy
Published: May 2021

Bicuspid aortic valve (BAV) is a congenital defect affecting 1–2% of the general population that is distinguished from the normal tricuspid aortic valve (TAV) by the existence of two, rather than three, functional leaflets (or cusps). BAV presents in different morphologic phenotypes based on the configuration of cusp fusion. The most common phenotypes are Type 1 (containing one raphe), where fusion between right coronary and left coronary cusps (BAV R/L) is the most common configuration followed by fusion between right coronary and non-coronary cusps (BAV R/NC). While anatomically different, BAV R/L and BAV R/NC configurations are both associated with abnormal hemodynamic and biomechanical environments. The natural history of BAV has shown that it is not necessarily the primary structural malformation that enforces the need for treatment in young adults, but the secondary onset of premature calcification in ~50% of BAV patients, that can lead to aortic stenosis. While an underlying genetic basis is a major pathogenic contributor of the structural malformation, recent studies have implemented computational models, cardiac imaging studies, and bench-top methods to reveal BAV-associated hemodynamic and biomechanical alterations that likely contribute to secondary complications. Contributions to the field, however, lack support for a direct link between the external valvular environment and calcific aortic valve disease in the setting of BAV R/L and R/NC BAV. Here we review the literature of BAV hemodynamics and biomechanics and discuss its previously proposed contribution to calcification. We also offer means to improve upon previous studies in order to further characterize BAV and its secondary complications.
Interpretability of Machine Learning Solutions in Public Healthcare: The CRISP-ML Approach
Authors: Kolyshkina Inna , Simoff Simeon
Published: May 2021

Public healthcare has a history of cautious adoption for artificial intelligence (AI) systems. The rapid growth of data collection and linking capabilities combined with the increasing diversity of the data-driven AI techniques, including machine learning (ML), has brought both ubiquitous opportunities for data analytics projects and increased demands for the regulation and accountability of the outcomes of these projects. As a result, the area of interpretability and explainability of ML is gaining significant research momentum. While there has been some progress in the development of ML methods, the methodological side has shown limited progress. This limits the practicality of using ML in the health domain: the issues with explaining the outcomes of ML algorithms to medical practitioners and policy makers in public health has been a recognized obstacle to the broader adoption of data science approaches in this domain. This study builds on the earlier work which introduced CRISP-ML, a methodology that determines the interpretability level required by stakeholders for a successful real-world solution and then helps in achieving it. CRISP-ML was built on the strengths of CRISP-DM, addressing the gaps in handling interpretability. Its application in the Public Healthcare sector follows its successful deployment in a number of recent real-world projects across several industries and fields, including credit risk, insurance, utilities, and sport. This study elaborates on the CRISP-ML methodology on the determination, measurement, and achievement of the necessary level of interpretability of ML solutions in the Public Healthcare sector. It demonstrates how CRISP-ML addressed the problems with data diversity, the unstructured nature of data, and relatively low linkage between diverse data sets in the healthcare domain. The characteristics of the case study, used in the study, are typical for healthcare data, and CRISP-ML managed to deliver on these issues, ensuring the required level of interpretability of the ML solutions discussed in the project. The approach used ensured that interpretability requirements were met, taking into account public healthcare specifics, regulatory requirements, project stakeholders, project objectives, and data characteristics. The study concludes with the three main directions for the development of the presented cross-industry standard process.
Effects of Incorporating Measured Leaf Optical Properties in Land Surface Models
Authors: Dong Wenzong , Yuan Hua , Zhang Ruqing , Li Hongmei , Huang Lina , Zhu Siguang , Peng Jingman , Dai Yongjiu
Published: May 2021

Leaf optical properties (LOPs, i.e., leaf reflectance and transmittance), as a fundamental property of vegetation, are a key parameter in the canopy radiative transfer process. LOPs have a direct impact on the surface solar radiation partition and further affect surface flux exchanges. Recent works have provided reliable LOP data and mentioned that notable differences exist between the prescribed LOP values in current land surface models and measured LOP values, especially in the near-infrared (NIR) band. To evaluate the effects of different LOP values in land surface modeling, we ran two land surface models (the Community Land Model and the Common Land Model) with their default prescribed and measured values to examine the differences in simulated surface radiation partitions and fluxes. Our analyses show that differences in LOP values can lead to a large discrepancy in albedo, radiation partition, sensible heat flux and net radiation simulations. By using the measured LOP values, in the boreal forest zone, Southeast China, and the eastern United States, both models have a significantly increased surface albedo in the NIR band, with the difference exceeding 10% during JJA. Thus, the measured LOP values can improve the negative albedo bias in the boreal forest zone during summertime. Moreover, both models simulate less net radiation with a maximum reduction of 11 W/m2 when incorporating the measured LOP values. Therefore, the total sensible heat flux can be reduced by as much as 11 W/m2. The results of this study emphasize that different LOP values can have a considerable effect on the surface radiation budget and sensible heat flux simulations which need attention in land surface model development. However, in current offline simulations, the measured LOP values cause slight changes in land surface temperatures and gross primary productivity (GPP).
Current and Future Roles of Circular RNAs in Normal and Pathological Endometrium
Authors: Tu Jiajie , Yang Huan , Chen Yu , Chen Yu , Chen He , Li Zhe , Li Lei , Zhang Yuanyuan , Chen Xiaochun , Yu Zhiying
Published: May 2021

The uterine endometrium, which lines the mammalian uterus, is essential for embryo implantation. This lining undergoes significant changes during sexual and menstrual cycles. The endometrium is also associated with hormone-related diseases such as endometriosis and endometrial cancer. Circular RNAs (circRNAs) play a role in various biological processes. Recent studies have determined that circRNAs function in both normal and pathological endometrial environments. Here, we review high-throughput studies pertaining to circRNAs as well as individual circRNAs active in the endometrium, in order to explore the myriad functions of circRNAs in the endometrium and mechanisms underlying these functions, from panoramic and individual perspectives. Owing to their abundant expression, stability, and small size, circRNAs have displayed potential usefulness as diagnostic markers and treatment targets for endometrial-related diseases. Therefore, the specific role of circRNAs in the endometrium warrants systematic investigation in the future.
Raman Spectroscopic Study on a CO2-CH4-N2 Mixed-Gas Hydrate System
Authors: Chuanhai Liu , Ran Chen , Baoyong Zhang , Qiang Wu , Qiang Zhang , Xia Gao , Qiong Wu
Published: May 2021

Accurate determination of the characteristics of coal mine gas separation products is the key for gas separation applications based on hydrate technology. Gas hydrates are synthesized from gases with two types of compositions (CO2-CH4-N2). The separation products were analyzed by in situ Raman spectroscopy. The crystal structure of the mixed-gas hydrate was determined, and the cage occupancy and hydration index were calculated based on the various vibrational modes of the molecules according to the “loose cage-tight cage” model and the Raman band area ratio combined with the van der Waals-Platteeuw model. The results show that the two mixed-gas hydrate samples both have a type I structure. Large cages of mixed-gas hydrate are mostly occupied by guest molecules, with large cage occupancies of 98.57 and 98.52%; however, small cages are not easy to occupy, with small cage occupancies of 29.93 and 33.87%. The average cage occupancies of these two hydrates are 81.41 and 82.36%, and the stability of the crystal structure of the mixed-gas hydrate in the presence of 75% CO2 is better than that of the mixed-gas hydrate in the presence of 70% CO2. The hydration indices of the two hydrate gas samples are 7.14 and 6.98, which are greater than the theoretical value of structure l.
Enabling Enduring Evidence-Based Policy for the Southern Ocean Through Cultural Arts Practices
Authors: Roberts Lisa , Kutay Cat , Melbourne-Thomas Jess , Petrou Katherina , Benson Tracey M. , Fiore Danae , Fletcher Paul , Johnson Ellery , Silk Melissa , Taberner Stephen , Filgueira Victor Vargas , Constable Andrew J.
Published: May 2021

This paper provides a perspective on how art and cross-cultural conversations can facilitate understanding of important scientific processes, outcomes and conclusions, using the Marine Ecosystem Assessment for the Southern Ocean (MEASO) as a case study. First, we reflect on our rationale and approach, describing the importance of deeper communication, such as through the arts, to the policy process; more enduring decisions are possible by engaging and obtaining perspectives through more than just a utilitarian lens. Second, we draw on the LivingData Website [http://www.livingdata.net.au] where art in all its forms is made to bridge differences in knowledge systems and their values, provide examples of how Indigenous knowledge and Western science can be complementary, and how Indigenous knowledge can show the difference between historical natural environmental phenomena and current unnatural phenomena, including how the Anthropocene is disrupting cultural connections with the environment that ultimately impact everyone. Lastly, we document the non-linear process of our experience and draw lessons from it that can guide deeper communication between disciples and cultures, to potentially benefit decision-making. Our perspective is derived as a collective from diverse backgrounds, histories, knowledge systems and values.
Pulse Effect of Precipitation: Spatial Patterns and Mechanisms of Soil Carbon Emissions
Authors: Jiang Zhaoxia , Bian Hongfeng , Xu Li , Li Mingxu , He Nianpeng
Published: May 2021

The rapid and strong release of CO2 caused by precipitation (known as the pulse effect) is a common phenomenon that significantly affects ecosystem C cycling. However, the degree to which the pulse effect occurs overlarge regional scales remains unclear. In this study, we conducted continuous and high-frequency measurements of soil CO2 release rates (Rs) for 48 h after simulated precipitation, along a precipitation gradient of different grassland types (i.e., meadow, typical, and desert) in Inner Mongolia, China. Pulse effects were assessed using the maximum Rs (Rsoil–max) and accumulated CO2 emissions (ARs–soil). Strong precipitation pulse effects were found in all sites; however, the effects differed among grassland types. In addition, an apparent decrease in both Rsoil–max and ARs–soil was observed from the east to west, i.e., along the decreasing precipitation gradient. ARs–soil values followed the order: temperate meadow grassland (0.097 mg C g–1 soil) > typical temperate grassland (0.081 mg C g–1 soil) > temperate desert grassland (0.040 mg C g–1 soil). Furthermore, Rsoil–max and ARs–soil were significantly positively correlated with soil quality (SOC, POC, and N, etc.; P < 0.01). ARs–soil (P < 0.05) and ARs–SOC (P < 0.01) were significantly affected. ARs–soil and ARs–SOC were also positively correlated with soil microbial biomass significantly (P < 0.05). Rsoil–max and ARs–soil had similar spatial variations and controlling mechanisms. These results greatly support the substrate supply hypothesis for the effects of precipitation pulses, and provide valuable information for predicting CO2 emissions. Our findings also verified the significant effect of soil CO2 release from precipitation pulses on the grasslands of arid and semi-arid regions. Our data provide a scientific basis for model simulations to better predict the responses of ecosystem carbon cycles in arid and semi-arid regions under predicted climate change scenarios.
Peritumoral Tertiary Lymphoid Structures Correlate With Protective Immunity and Improved Prognosis in Patients With Hepatocellular Carcinoma
Authors: Li Hui , Liu Hailing , Fu Hongyuan , Li Jiaxin , Xu Lin , Wang Genshu , Wu Hong
Published: May 2021

The existence of intratumoral tertiary lymphoid structure (iTLS) has been reported to correlative with favorable clinical outcomes for patients with hepatocellular carcinoma (HCC). However, little is known about the role of peritumoral TLS (pTLS). This study aimed to investigate the prognostic role of pTLS either alone or jointly with iTLS and the potential association with local immune response in HCC. The formation and cellular composition of TLS was evaluated by hematoxylin & eosin and immunohistochemistry. Evaluation of tumor-infiltrating immune cells and formation of germinal center (GC) inside TLS was performed by immunohistochemistry. The gene expression profiles were analyzed by real-time PCR. In a total of 360 patients from two independent cohorts, the pTLS was identified in most, whereas iTLS could be observed in only approximately 30% of HCC specimens. Patients with high pTLS densities were associated with improved outcomes, those present with characteristic morphology of GC, particularly, showing an even better prognosis. The combination of pTLS and iTLS allowed the identification of patients with best prognosis. Tumors with high pTLS density showed significantly increased expression of Th1-, Th17- and immune suppression-related genes, as well as significantly higher infiltration of CD3+, CD8+ and CD20+ cells and lower infiltration of FOXP3+, CD68+ and PD1+ cells. Conclusively, we provide evidence that pTLS is associated with intratumoral immune infiltration, highlighting the dynamic interplay between pTLS and immune cells recruitment. High pTLS density links to a tumor microenvironment with an active immune reaction and improved patient survival and represents a promising prognostic biomarker for HCC.
Innate Immune Reconstitution in Humanized Bone Marrow-Liver-Thymus (HuBLT) Mice Governs Adaptive Cellular Immune Function and Responses to HIV-1 Infection
Authors: Garcia-Beltran Wilfredo F. , Claiborne Daniel T. , Maldini Colby R. , Phelps Meredith , Vrbanac Vladimir , Karpel Marshall E. , Krupp Katharine L. , Power Karen A. , Boutwell Christian L. , Balazs Alejandro B. , Tager Andrew M. , Altfeld Marcus , Allen Todd M.
Published: May 2021

Humanized bone marrow-liver-thymus (HuBLT) mice are a revolutionary small-animal model that has facilitated the study of human immune function and human-restricted pathogens, including human immunodeficiency virus type 1 (HIV-1). These mice recapitulate many aspects of acute and chronic HIV-1 infection, but exhibit weak and variable T-cell responses when challenged with HIV-1, hindering our ability to confidently detect HIV-1–specific responses or vaccine effects. To identify the cause of this, we comprehensively analyzed T-cell development, diversity, and function in HuBLT mice. We found that virtually all HuBLT were well-reconstituted with T cells and had intact TCRβ sequence diversity, thymic development, and differentiation to memory and effector cells. However, there was poor CD4+ and CD8+ T-cell responsiveness to physiologic stimuli and decreased TH1 polarization that correlated with deficient reconstitution of innate immune cells, in particular monocytes. HIV-1 infection of HuBLT mice showed that mice with higher monocyte reconstitution exhibited greater CD8+ T cells responses and HIV-1 viral evolution within predicted HLA-restricted epitopes. Thus, T-cell responses to immune challenges are blunted in HuBLT mice due to a deficiency of innate immune cells, and future efforts to improve the model for HIV-1 immune response and vaccine studies need to be aimed at restoring innate immune reconstitution.
Treatment-Induced BAFF Expression and B Cell Biology in Multiple Sclerosis
Authors: Smets Ide , Prezzemolo Teresa , Imbrechts Maya , Mallants Klara , Mitera Tania , Humblet-Baron Stéphanie , Dubois Bénédicte , Matthys Patrick , Liston Adrian , Goris An
Published: May 2021

Although fingolimod and interferon-β are two mechanistically different multiple sclerosis (MS) treatments, they both induce B cell activating factor (BAFF) and shift the B cell pool towards a regulatory phenotype. However, whether there is a shared mechanism between both treatments in how they influence the B cell compartment remains elusive. In this study, we collected a cross-sectional study population of 112 MS patients (41 untreated, 42 interferon-β, 29 fingolimod) and determined B cell subsets, cell-surface and RNA expression of BAFF-receptor (BAFF-R) and transmembrane activator and cyclophilin ligand interactor (TACI) as well as plasma and/or RNA levels of BAFF, BAFF splice forms and interleukin-10 (IL-10) and -35 (IL-35). We added an in vitro B cell culture with four stimulus conditions (Medium, CpG, BAFF and CpG+BAFF) for untreated and interferon-β treated patients including measurement of intracellular IL-10 levels. Our flow experiments showed that interferon-β and fingolimod induced BAFF protein and mRNA expression (P ≤ 3.15 x 10-4) without disproportional change in the antagonizing splice form. Protein BAFF correlated with an increase in transitional B cells (P = 5.70 x 10-6), decrease in switched B cells (P = 3.29 x 10-4), and reduction in B cell-surface BAFF-R expression (P = 2.70 x 10-10), both on TACI-positive and -negative cells. TACI and BAFF-R RNA levels remained unaltered. RNA, plasma and in vitro experiments demonstrated that BAFF was not associated with increased IL-10 and IL-35 levels. In conclusion, treatment-induced BAFF correlates with a shift towards transitional B cells which are enriched for cells with an immunoregulatory function. However, BAFF does not directly influence the expression of the immunoregulatory cytokines IL-10 and IL-35. Furthermore, the post-translational mechanism of BAFF-induced BAFF-R cell surface loss was TACI-independent. These observations put the failure of pharmaceutical anti-BAFF strategies in perspective and provide insights for targeted B cell therapies.
Lung Transplantation and the Era of the Sensitized Patient
Authors: Young Katherine A. , Ali Hakim A. , Beermann Kristi J. , Reynolds John M. , Snyder Laurie D.
Published: May 2021

Long term outcomes in lung transplant are limited by the development of chronic lung allograft dysfunction (CLAD). Within the past several decades, antibody-mediated rejection (AMR) has been recognized as a risk factor for CLAD. The presence of HLA antibodies in lung transplant candidates, “sensitized patients” may predispose patients to AMR, CLAD, and higher mortality after transplant. This review will discuss issues surrounding the sensitized patient, including mechanisms of sensitization, implications within lung transplant, and management strategies.
Optimizing Safe Dental Practice During the COVID-19 Pandemic: Recommendations Based on a Guide Developed for Dental Practices in China
Authors: Li Li , Zeng Mianyan , Chen Xiao , Cai Shuman , Xu Cuixia , Xia Wei , Jiang Lijun , Zou Xiaoyan , Chen Pei , Rong Mingdeng
Published: May 2021

The current global coronavirus disease 2019 (COVID-19) outbreak is still exerting severe global implications, and its development in various regions is complex and variable. The high risk of cross-infection poses a great challenge to the dental practice environment; it is therefore urgent to develop a set of pandemic prevention measures to ensure dental practice safety during the COVID-19 outbreak. Therefore, we combined the epidemiological characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), public emergency measures for COVID-19, characteristics of dental practice, and relevant literature reports to develop a set of dynamic practice measures for dental practices in high-, medium-, and low-risk areas affected by COVID-19. This will help dental practices to achieve standard prevention and ensure their safe and smooth operation during the pandemic. It is hoped that these measures will provide a reference basis for dental hospitals and dental clinics in their care and pandemic prevention work.
Teledermatology Adaptations in the COVID-19 Era
Authors: Edwards Harrison A. , Shen Xiaohua , Soyer H. Peter
Published: May 2021

The COVID-19 pandemic has required health services worldwide to adapt to dramatically changing healthcare needs and risks across all medical specialties. In the dermatology department at Princess Alexandra Hospital, Brisbane, Australia, we developed and implemented a teledermatology system with 1 week's notice to help reduce infection risk bidirectionally, while saving patients many hours of travel and waiting time with acceptable technological substitutes for the clinical encounters. In this study, we report the efficacy and tolerability of our telephone consultation and store and forward imaging system, including patient experience from validated survey data. Our design, implementation and usage of a remote-default system provides experience and lessons to draw upon in developing future telemedicine systems to address dermatology service maldistribution – an issue affecting large areas of Australia – as well as preparedness for future infection mitigation requirements.
Chess Not Checkers: Complexities Within the Myeloid Response to the Acute Kidney Injury Syndrome
Authors: Nash William T. , Okusa Mark D.
Published: May 2021

Immune dysregulation in acute kidney injury (AKI) is an area of intense interest which promises to enhance our understanding of the disease and how to manage it. Macrophages are a heterogeneous and dynamic population of immune cells that carry out multiple functions in tissue, ranging from maintenance to inflammation. As key sentinels of their environment and the major immune population in the uninjured kidney, macrophages are poised to play an important role in the establishment and pathogenesis of AKI. These cells have a profound capacity to orchestrate downstream immune responses and likely participate in skewing the kidney environment toward either pathogenic inflammation or injury resolution. A clear understanding of macrophage and myeloid cell dynamics in the development of AKI will provide valuable insight into disease pathogenesis and options for intervention. This review considers evidence in the literature that speaks to the role and regulation of macrophages and myeloid cells in AKI. We also highlight barriers or knowledge gaps that need to be addressed as the field advances.
Inactivation of Latent HIV-1 Proviral DNA Using Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 Treatment and the Assessment of Off-Target Effects
Authors: Xu Yufan , Peng Xiaorong , Zheng Yanghao , Jin Changzhong , Lu Xiangyun , Han Dating , Fu Haijing , Chen Chaoyu , Wu Nanping
Published: May 2021

Viral DNA integrated in host cells is a major barrier to completely curing HIV-1. However, genome editing using the recently developed technique of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 has the potential to eradicate HIV-1. The present study aimed to use a lentiviral vector-based CRISPR/Cas9 system combined with dual-small/single guide RNAs (sgRNAs) to attack HIV-1 DNA in the latency reactivation model J-Lat 10.6 cell line and to assess off-target effects using whole-genome sequencing (WGS). We designed 12 sgRNAs targeting HIV-1 DNA, and selected high-efficiency sgRNAs for further pairwise combinations after a preliminary evaluation of the editing efficiency. Three combinations of dual-sgRNAs/Cas9 with high editing efficiency were screened successfully from multiple combinations. Among these combinations, the incidences of insertions and deletions in the sgRNA-targeted regions reached 76% and above, and no credible off-target sites were detected using WGS. The results provided comprehensive basic experimental evidence and methodological recommendations for future personalized HIV-1 treatment using CRISPR/Cas9 genome editing technology.
Soil Fungal Community Structure in Boreal Pine Forests: From Southern to Subarctic Areas of Finland
Authors: Qu Zhao-Lei , Santalahti Minna , Köster Kajar , Berninger Frank , Pumpanen Jukka , Heinonsalo Jussi , Sun Hui
Published: May 2021

The boreal forest environment plays an important role in the global C cycle due to its high carbon storage capacity. However, relatively little is known about the forest fungal community at a regional scale in boreal forests. In the present study, we have re-analyzed the data from our previous studies and highlighted the core fungal community composition and potential functional groups in three forests dominated by Scots pine (Pinus sylvestris L.) in Finland, and identified the fungal generalists that appear across geographic locations despite differences in local conditions. The three forests represent subarctic, northern and southern boreal forest, and are all in an un-managed state without human interference or management. The subarctic and northern areas are subject to reindeer grazing. The results showed that the three locations formed distinct fungal community structures (P < 0.05). Compared to the two northern locations, the southern boreal forest harbored a greater abundance of Zygomycota, Lactarius, Mortierella Umbelopsis, and Tylospora, in which aspect there were no differences between the two northern forests. Cortinarius, Piloderma, and Suillus were the core fungal genera in the boreal Scots pine forest. Functionally, the southern boreal forest harbored a greater abundance of saprotroph, endophytes and fungal parasite-lichen, whereas a greater abundance of ectomycorrhizal fungi was observed in the northern boreal forests. Moreover, the pathotroph and wood saprotrophs were commonly present in these three regions. The three locations formed two distinct fungal community functional structures, by which the southern forest was clearly separated from the two northern forests, suggesting a distance–decay relationship via geographic location. This study provides useful information for better understanding the common fungal communities and functions in boreal forests in different geographical locations.
Taurine Protects C2C12 Myoblasts From Impaired Cell Proliferation and Myotube Differentiation Under Cisplatin-Induced ROS Exposure
Authors: Zhou Lin , Lu Ruohan , Huang Caihua , Lin Donghai
Published: May 2021

In cancer patients, chemotherapeutic medication induces aberrant ROS (reactive oxygen species) accumulation in skeletal muscles, resulting in myofiber degradation, muscle weakness, and even cachexia, which further leads to poor therapeutic outcomes. Acting as an antioxidant, taurine is extensively used to accelerate postexercise muscle recovery in athletes. The antioxidant effects of taurine have been shown in mature myotubes and myofibers but not yet in myoblasts, the myotube precursor. The proliferation and differentiation ability of myoblasts play a very important role in myofiber repair and regeneration, which is usually impaired during chemotherapeutics in cancer patients as well. Here, we explored the effects of taurine supplementation on C2C12 myoblasts exposed to cisplatin-induced ROS. We found that cisplatin treatment led to dramatically decreased cell viability; accumulated ROS level; down-regulated expressions of MyoD1 (myoblast determination protein 1), myogenin, and MHC (myosin heavy chain); and impaired myotube differentiation in myoblasts. Significantly, taurine supplementation protected myoblasts against cisplatin-induced cell viability decrease, promoted cellular ROS clearance, and, most importantly, preserved the expressions of MyoD1, myogenin, and MHC as well as myotube differentiation ability. We further conducted NMR-based metabolomic analysis to clarify the underlying molecular mechanisms. We identified 14 characteristic metabolites primarily responsible for the discrimination of metabolic profiles between cisplatin-treated cells and normal counterparts, including increased levels of BCAAs (branched-chain amino acids: leucine and isoleucine), alanine, glycine, threonine, glucose, ADP (adenosine diphosphate), phenylalanine, and PC (O-phosphocholine), and decreased levels of lysine, β-alanine, choline, GPC (sn-glycero-3-phosphocholine), and myo-inositol. Evidently, taurine supplementation partially reversed the changing trends of several metabolites (isoleucine, threonine, glycine, PC, β-alanine, lysine, and myo-inositol). Furthermore, taurine supplementation promoted the proliferation and myotube differentiation of myoblasts by alleviating cellular catabolism, facilitating GSH (reduced glutathione) biosynthesis, improving glucose utilization and TCA (tricarboxylic acid) cycle anaplerosis, and stabilizing cellular membranes. Our results demonstrated the protective effects of taurine on cisplatin-impaired myoblasts and elucidated the mechanistic rationale for the use of taurine to ameliorate muscle toxicity in clinical chemotherapy cancer patients.