bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and Validation of a Prognostic Autophagy-Related Gene Pair Index Related to Tumor-Infiltrating Lymphocytes in Early-Stage Lung Adenocarcinoma
Authors: Wang Zi-Hao , Li Yu , Zhang Pei , Xiang Xuan , Wei Xiao-Shan , Niu Yi-Ran , Ye Lin-Lin , Peng Wen-Bei , Zhang Si-Yu , Xue Qian-Qian , Zhou Qiong
Published: September 2021

The role of autophagy in lung cancer is context-dependent and complex. Recent studies have reported the important role of autophagy in tumor immune escape. However, the association between autophagy and tumor-infiltrating lymphocytes (TILs) in early-stage lung adenocarcinoma (LUAD) remains unclear. In this study, we aimed to develop and validate the autophagy-related gene pair index (ATGPI) and autophagy clinical prognostic index (ACPI) in multiple LUAD cohorts, including The Cancer Genome Atlas (TCGA) cohort, Gene Expression Omnibus cohorts, and one cohort from Union Hospital, Wuhan (UH cohort), using a Cox proportional hazards regression model with the least absolute shrinkage and selection operator. Multivariate Cox regression analysis demonstrated that there was a significant difference in overall survival (OS) between patients with high and low ATGPI in the testing [hazard ratio (HR) = 1.97; P < 0.001] and TCGA validation (HR = 2.25; P < 0.001) cohorts. Time-dependent receiver operating characteristic curve analysis was also performed. We found that high ATGPI could accurately identify patients with early-stage LUAD with shorter OS, with the areas under the curve of 0.703 and 0.676 in the testing and TCGA validation cohorts, respectively. Concordance index (C-index) was used to evaluate the efficiency of ATGPI and ACPI. The C-index of ACPI was higher than that of ATGPI in the testing (0.71 vs. 0.66; P < 0.001), TCGA validation (0.69 vs. 0.65; P = 0.028), and UH (0.80 vs. 0.70; P = 0.015) cohorts. TIL analysis demonstrated that the proportions of tumor-infiltrating CD4+ T cells were lower in the high-ATGPI group than in the low-ATGPI group in both the TCGA validation and UH cohorts. These results indicate the potential clinical use of ATG signatures which are associated with TILs, in identifying patients with early-stage LUAD with different OS.
Mitochondrial Impairment by MitoBloCK-6 Inhibits Liver Cancer Cell Proliferation
Authors: Kabiri Yaschar , Fuhrmann Anna , Becker Anna , Jedermann Luisa , Eberhagen Carola , König Ann-Christine , Silva Tiago Barros , Borges Fernanda , Hauck Stefanie M. , Michalke Bernhard , Knolle Percy , Zischka Hans
Published: September 2021

Augmenter of liver regeneration (ALR) is a critical multi-isoform protein with its longer isoform, located in the mitochondrial intermembrane space, being part of the mitochondrial disulfide relay system (DRS). Upregulation of ALR was observed in multiple forms of cancer, among them hepatocellular carcinoma (HCC). To shed light into ALR function in HCC, we used MitoBloCK-6 to pharmacologically inhibit ALR, resulting in profound mitochondrial impairment and cancer cell proliferation deficits. These effects were mostly reversed by supplementation with bioavailable hemin b, linking ALR function to mitochondrial iron homeostasis. Since many tumor cells are known for their increased iron demand and since increased iron levels in cancer are associated with poor clinical outcome, these results help to further advance the intricate relation between iron and mitochondrial homeostasis in liver cancer.
Chemical Inhibition of Apurinic-Apyrimidinic Endonuclease 1 Redox and DNA Repair Functions Affects the Inflammatory Response via Different but Overlapping Mechanisms
Authors: Oliveira Thais Teixeira , Fontes-Dantas Fabrícia Lima , de Medeiros Oliveira Rayssa Karla , Pinheiro Daniele Maria Lopes , Coutinho Leonam Gomes , da Silva Vandeclecio Lira , de Souza Sandro José , Agnez-Lima Lucymara Fassarella
Published: September 2021

The presence of oxidized DNA lesions, such as 7,8-dihydro-8-oxoguanine (8-oxoG) and apurinic/apyrimidinic sites (AP sites), has been described as epigenetic signals that are involved in gene expression control. In mammals, Apurinic-apyrimidinic endonuclease 1/Redox factor-1 (APE1/Ref-1) is the main AP endonuclease of the base excision repair (BER) pathway and is involved in active demethylation processes. In addition, APE1/Ref-1, through its redox function, regulates several transcriptional factors. However, the transcriptional control targets of each APE1 function are not completely known. In this study, a transcriptomic approach was used to investigate the effects of chemical inhibition of APE1/Ref-1 redox or DNA repair functions by E3330 or methoxyamine (MX) in an inflammatory cellular model. Under lipopolysaccharide (LPS) stimulation, both E3330 and MX reduced the expression of some cytokines and chemokines. Interestingly, E3330 treatment reduced cell viability after 48 h of the treatment. Genes related to inflammatory response and mitochondrial processes were downregulated in both treatments. In the E3330 treatment, RNA processing and ribosome biogenesis genes were downregulated, while they were upregulated in the MX treatment. Furthermore, in the E3330 treatment, the cellular stress response was the main upregulated process, while the cellular macromolecule metabolic process was observed in MX-upregulated genes. Nuclear respiratory factor 1 (NRF1) was predicted to be a master regulator of the downregulated genes in both treatments, while the ETS transcription factor ELK1 (ELK1) was predicted to be a master regulator only for E3330 treatment. Decreased expression of ELK1 and its target genes and a reduced 28S/18S ratio were observed, suggesting impaired rRNA processing. In addition, both redox and repair functions can affect the expression of NRF1 and GABPA target genes. The master regulators predicted for upregulated genes were YY1 and FLI1 for the E3330 and MX treatments, respectively. In summary, the chemical inhibition of APE1/Ref-1 affects gene expression regulated mainly by transcriptional factors of the ETS family, showing partial overlap of APE1 redox and DNA repair functions, suggesting that these activities are not entirely independent. This work provides a new perspective on the interaction between APE1 redox and DNA repair activity in inflammatory response modulation and transcription.
Development of Extracellular Vesicle Therapeutics: Challenges, Considerations, and Opportunities
Authors: Claridge Bethany , Lozano Jonathan , Poh Qi Hui , Greening David W.
Published: September 2021

Extracellular vesicles (EVs) hold great promise as therapeutic modalities due to their endogenous characteristics, however, further bioengineering refinement is required to address clinical and commercial limitations. Clinical applications of EV-based therapeutics are being trialed in immunomodulation, tissue regeneration and recovery, and as delivery vectors for combination therapies. Native/biological EVs possess diverse endogenous properties that offer stability and facilitate crossing of biological barriers for delivery of molecular cargo to cells, acting as a form of intercellular communication to regulate function and phenotype. Moreover, EVs are important components of paracrine signaling in stem/progenitor cell-based therapies, are employed as standalone therapies, and can be used as a drug delivery system. Despite remarkable utility of native/biological EVs, they can be improved using bio/engineering approaches to further therapeutic potential. EVs can be engineered to harbor specific pharmaceutical content, enhance their stability, and modify surface epitopes for improved tropism and targeting to cells and tissues in vivo. Limitations currently challenging the full realization of their therapeutic utility include scalability and standardization of generation, molecular characterization for design and regulation, therapeutic potency assessment, and targeted delivery. The fields’ utilization of advanced technologies (imaging, quantitative analyses, multi-omics, labeling/live-cell reporters), and utility of biocompatible natural sources for producing EVs (plants, bacteria, milk) will play an important role in overcoming these limitations. Advancements in EV engineering methodologies and design will facilitate the development of EV-based therapeutics, revolutionizing the current pharmaceutical landscape.
Crassifolins Q−W: Clerodane Diterpenoids From Croton crassifolius With Anti-Inflammatory and Anti-Angiogenesis Activities
Authors: Li Canjie , Sun Xin , Yin Wenjing , Zhan Zhaochun , Tang Qing , Wang Wenzhi , Zhuo Xuefang , Wu Zhongnan , Zhang Haipeng , Li Yaolan , Zhang Yubo , Wang Guocai
Published: September 2021

Seven new clerodane diterpenoids, crassifolins Q−W (1–7), along with five known analogues (8–12), were isolated from the roots ofCroton crassifolius. Their structures were identified by comprehensive spectroscopic analysis (UV, IR, NMR, and HR-ESI-MS), and their absolute configurations were determined by ECD spectra and X-ray crystallography. The activities of compounds1–5against inflammatory cytokines IL-6 and TNF-αlevels on LPS-induced RAW 264.7 macrophages were assessed, and compound5showed the most significant activity with the secretion levels of IL-6 and TNF-αat 32.78 and 12.53%, respectively. Moreover, compounds1–5were screened for their anti-angiogenesis using a human umbilical vein endothelial cellsin vitromode; the results showed all of them exhibited obvious anti-angiogenesis activities, in particular, compound5showed the strongest anti-angiogenesis effect in the range of 6.25–50 μM.
Analysis of Susceptibility to the Antimicrobial and Anti-Biofilm Activity of Human Milk Lactoferrin in Clinical Strains of Streptococcus agalactiae With Diverse Capsular and Sequence Types
Authors: Lu Jacky , Guevara Miriam A. , Francis Jamisha D. , Spicer Sabrina K. , Moore Rebecca E. , Chambers Schuyler A. , Craft Kelly M. , Manning Shannon D. , Townsend Steven D. , Gaddy Jennifer A.
Published: September 2021

Group BStreptococcus(GBS) is one of the leading infection-related causes of adverse maternal and neonatal outcomes. This includes chorioamnionitis, which leads to preterm ruptures of membranes and can ultimately result in preterm or stillbirth. Infection can also lead to maternal and neonatal sepsis that may contribute to mortality. Currently, treatment for GBS infection include a bolus of intrapartum antibiotic prophylaxis to mothers testing positive for GBS colonization during late pregnancy. Lactoferrin is an antimicrobial peptide expressed in human breast milk, mucosal epithelia, and secondary granules of neutrophils. We previously demonstrated that lactoferrin possesses antimicrobial and antibiofilm properties against several strains of GBS. This is largely due to the ability of lactoferrin to bind and sequester iron. We expanded upon that study by assessing the effects of purified human breast milk lactoferrin against a panel of phenotypically and genetically diverse isolates of GBS. Of the 25 GBS isolates screened, lactoferrin reduced bacterial growth in 14 and biofilm formation in 21 strains. Stratifying the data, we observed that colonizing strains were more susceptible to the growth inhibition activity of lactoferrin than invasive isolates at lactoferrin concentrations between 250-750 µg/mL. Treatment with 750 µg/mL of lactoferrin resulted in differences in bacterial growth and biofilm formation between discrete sequence types. Differences in bacterial growth were also observed between capsular serotypes 1a and III. Maternally isolated strains were more susceptible to lactoferrin with respect to bacterial growth, but not biofilm formation, compared to neonatal sepsis isolates. Finally, high biofilm forming GBS strains were more impacted by lactoferrin across all isolates tested. Taken together, this study demonstrates that lactoferrin possesses antimicrobial and antibiofilm properties against a wide range of GBS isolates, with maternally isolated colonizing strains being the most susceptible.
Lipocalin 2 Is a Regulator During Macrophage Polarization Induced by Soluble Worm Antigens
Authors: Shen Hanyu , Wang Ziheng , Huang Ailong , Zhu Dandan , Sun Pingping , Duan Yinong
Published: September 2021

Caused by schistosomes, the human schistosomiasis is a tropical zoonotic parasitic disease. Pathologically, it occurs most often in the intestines and the liver, the sites ofSchistosoma japonicumegg accumulation. The parasites’ produced eggs cause the main pathology in patients. Deposited parasite eggs in the liver induce the production of multiple cytokines that mediate the immune response, which in turn leads to granulomatous responses and liver fibrosis. These impact the hosts’ quality of life and health status, resulting in severe morbidity and even mortality. In this study, differentially expressed genes (DEGs) between ordinary samples and three 6- week infected mice were mined from microarray analysis based on the limma package. In total, we excavated the differential expression LCN2 was exhibited high expressions profile in GSE59276, GSE61376 demonstrated the result. Furthermore, CIBERSORT suggested detailed analysis of the immune subtype distribution pattern.In vivoexperiments like real-time quantitative PCR, immunohistochemical (IHC) staining, and immunofluorescence (IF) demonstrated the expressions of LCN2 was significantly upregulated inS. japonicum–infected mice liver tissues and located in macrophages. Previous studies have shown that macrophages act as the first line of defense during schistosome infection and are an important part of liver granuloma. We usedS. japonicumsoluble worm antigens (SWA) to induce RAW264.7 cells to construct anin vitroinflammatory model. The current study aimed to investigate whether the NF-κB signaling network is involved in LCN2 upregulation induced by SWA and whether LCN2 can promote M1 polarization of macrophages under SWA treatment. Our research work suggests that LCN2 is significant in the development of early infection caused byS. japonicumand is of great value for further exploration. Collectively, the findings indicated that SWA promoted the expression of LCN2 and promoted M1 polarization of macrophagesviathe upregulation of NF-κB signaling pathway. Our findings demonstrate that NF-κB/LCN2 is necessary for migration and phagocytosis of M1 macrophages in response to SWA infection. Our study highlights the essential role of NF-κB/LCN2 in early innate immune response to infection.
Accuracy of Physicians Interpreting Photoplethysmography and Electrocardiography Tracings to Detect Atrial Fibrillation: INTERPRET-AF
Authors: Gruwez Henri , Evens Stijn , Proesmans Tine , Duncker David , Linz Dominik , Heidbuchel Hein , Manninger Martin , Vandervoort Pieter , Haemers Peter , Pison Laurent
Published: September 2021

Aims: This study aims to compare the performance of physicians to detect atrial fibrillation (AF) based on photoplethysmography (PPG), single-lead ECG and 12-lead ECG, and to explore the incremental value of PPG presentation as a tachogram and Poincaré plot, and of algorithm classification for interpretation by physicians.

Methods and Results: Email invitations to participate in an online survey were distributed among physicians to analyse almost simultaneously recorded PPG, single-lead ECG and 12-lead ECG traces from 30 patients (10 in sinus rhythm (SR), 10 in SR with ectopic beats and 10 in AF). The task was to classify the readings as ‘SR', ‘ectopic/missed beats', ‘AF', ‘flutter' or ‘unreadable'. Sixty-five physicians detected or excluded AF based on the raw PPG waveforms with 88.8% sensitivity and 86.3% specificity. Additional presentation of the tachogram plus Poincaré plot significantly increased sensitivity and specificity to 95.5% (P < 0.001) and 92.5% (P < 0.001), respectively. The algorithm information did not further increase the accuracy to detect AF (sensitivity 97.5%, P = 0.556; specificity 95.0%, P = 0.182). Physicians detected AF on single-lead ECG tracings with 91.2% sensitivity and 93.9% specificity. Diagnostic accuracy was also not optimal on full 12-lead ECGs (93.9 and 98.6%, respectively). Notably, there was no significant difference between the performance of PPG waveform plus tachogram and Poincaré, compared to a single-lead ECG to detect or exclude AF (sensitivity P = 0.672; specificity P = 0.536).

Conclusion: Physicians can detect AF on a PPG output with equivalent accuracy compared to single-lead ECG, if the PPG waveforms are presented together with a tachogram and Poincaré plot and the quality of the recordings is high.
Advances in Cardiotoxicity Induced by Altered Mitochondrial Dynamics and Mitophagy
Authors: Yin Yiyuan , Shen Haitao
Published: September 2021

Mitochondria are the most abundant organelles in cardiac cells, and are essential to maintain the normal cardiac function, which requires mitochondrial dynamics and mitophagy to ensure the stability of mitochondrial quantity and quality. When mitochondria are affected by continuous injury factors, the balance between mitochondrial dynamics and mitophagy is broken. Aging and damaged mitochondria cannot be completely removed in cardiac cells, resulting in energy supply disorder and accumulation of toxic substances in cardiac cells, resulting in cardiac damage and cardiotoxicity. This paper summarizes the specific underlying mechanisms by which various adverse factors interfere with mitochondrial dynamics and mitophagy to produce cardiotoxicity and emphasizes the crucial role of oxidative stress in mitophagy. This review aims to provide fresh ideas for the prevention and treatment of cardiotoxicity induced by altered mitochondrial dynamics and mitophagy.
Connected Hearing Devices and Audiologists: The User-Centered Development of Digital Service Innovations
Authors: Luengen Marie , Garrelfs Christopher , Adiloǧlu Kamil , Krueger Melanie , Cauchi Benjamin , Markert Uwe , Typlt Marei , Kinkel Martin , Schultz Carsten
Published: September 2021

Today, medical technology manufacturers enter the service market through the development of digital service innovations. In the field of audiology, these developments increasingly shift the service capacities from audiologists to manufacturers and technical systems. However, the technology-driven developments of manufacturers lack acceptance of hearing device users and undermine the important role of audiologists within the service provision. By following a user-centered design approach in order to deal with the technological and social challenges of disruptive services, we aim to develop service innovations on an integrated service platform in the field of tele-audiology. To ensure the acceptance of technology-driven service innovations among hearing device users and audiologists, we systematically integrated these actors in a participatory innovation process. With qualitative and quantitative data we identified several requirements and preferences for different service innovations in the field of tele-audiology. According to the preferences of the different actors, we proposed a service platform approach based on a connected hearing device in three pillars of application: 1) one-to-one (1:1) service innovations based on a remote fitting concept directly improve the availability of services offered by audiologists without being physically present. Based on this, 2) one-to-many (1:N) service innovations allow the use of the connected hearing device as an indirect data source for training a machine learning algorithm that empowers users through the automation of service processes. A centralized server system collects the data and performs the training of this algorithm. The optimized algorithm is provided to the connected hearing devices to perform automatic acoustic scene classification. This in turn allows optimization of the hearing devices within each acoustic scene. After the user-centered development of the different service innovations which are designed to converge on an integrated service platform, we experimentally evaluated the functionality and applicability of the system as well as the associated role models between the technical system, the hearing device users and audiologists. As a future outlook, we show potentials to use the connected hearing device for 3) cross-industry (N:M) service innovations in contexts outside the healthcare domain and give practical implications for the market launch of successful service innovations in the field of tele-audiology.
Exploring the Past Biosphere of Chew Bahir/Southern Ethiopia: Cross-Species Hybridization Capture of Ancient Sedimentary DNA from a Deep Drill Core
Authors: Krueger Johanna , Foerster Verena , Trauth Martin H. , Hofreiter Michael , Tiedemann Ralph
Published: September 2021

Eastern Africa has been a prime target for scientific drilling because it is rich in key paleoanthropological sites as well as in paleolakes, containing valuable paleoclimatic information on evolutionary time scales. The Hominin Sites and Paleolakes Drilling Project (HSPDP) explores these paleolakes with the aim of reconstructing environmental conditions around critical episodes of hominin evolution. Identification of biological taxa based on their sedimentary ancient DNA (sedaDNA) traces can contribute to understand past ecological and climatological conditions of the living environment of our ancestors. However, sedaDNA recovery from tropical environments is challenging because high temperatures, UV irradiation, and desiccation result in highly degraded DNA. Consequently, most of the DNA fragments in tropical sediments are too short for PCR amplification. We analyzed sedaDNA in the upper 70 m of the composite sediment core of the HSPDP drill site at Chew Bahir for eukaryotic remnants. We first tested shotgun high throughput sequencing which leads to metagenomes dominated by bacterial DNA of the deep biosphere, while only a small fraction was derived from eukaryotic, and thus probably ancient, DNA. Subsequently, we performed cross-species hybridization capture of sedaDNA to enrich ancient DNA (aDNA) from eukaryotic remnants for paleoenvironmental analysis, using established barcoding genes (cox1 and rbcL for animals and plants, respectively) from 199 species that may have had relatives in the past biosphere at Chew Bahir. Metagenomes yielded after hybridization capture are richer in reads with similarity to cox1 and rbcL in comparison to metagenomes without prior hybridization capture. Taxonomic assignments of the reads from these hybridization capture metagenomes also yielded larger fractions of the eukaryotic domain. For reads assigned to cox1, inferred wet periods were associated with high inferred relative abundances of putative limnic organisms (gastropods, green algae), while inferred dry periods showed increased relative abundances for insects. These findings indicate that cross-species hybridization capture can be an effective approach to enhance the information content of sedaDNA in order to explore biosphere changes associated with past environmental conditions, enabling such analyses even under tropical conditions.
OSL Chronology of the Siling Co Paleolithic Site in Central Tibetan Plateau
Authors: Luo Lan , Lai Zhongping , Zheng Wenhao , Xu Yantian , Yu Lupeng , Huang Chang , Tu Hua
Published: September 2021

When and how was the Tibetan Plateau (TP), one of the least habitable regions on Earth, occupied by humans are important questions in the research of human evolution. Among tens of Paleolithic archaeological sites discovered over the past decades, only five are considered coeval with or older than the Last Glacial Maximum (LGM, ∼27–19 ka). As one of them, the Siling Co site in the central TP was previously announced to be ∼40–30 ka based on radiocarbon dating and stratigraphic correlation. Given the loose chronological constraint in previous studies, we here re-examined the chronology of the Siling Co site with the optically stimulated luminescence (OSL) dating technique. Four sections from the paleo-shoreline at an elevation of ∼4,600 m in southeastern Siling Co were investigated, with stone artifacts found from the ground surface. Dating results of nine samples delineated the age of ∼4,600 m paleo-shoreline to be ∼10–7 ka (∼8.54 ± 0.21 ka in average). This age indicates that the Siling Co site is not earlier than the early Holocene, much younger than the former age. The revised age of the Siling Co site is consistent with the wet and humid climate conditions on the TP during the early Holocene.
The Origin and 3D Architecture of a Km-Scale Deep-Water Scour-Fill: Example From the Skoorsteenberg Fm, Karoo Basin, South Africa
Authors: Hansen L. A. S. , Healy R. S. , Gomis-Cartesio L. , Lee D. R. , Hodgson D. M. , Pontén A. , Wild R. J.
Published: September 2021

Scours, and scour fields, are common features on the modern seafloor of deep-marine systems, particularly downstream of submarine channels, and in channel-lobe-transition-zones. High-resolution images of the seafloor have improved the documentation of the large scale, coalescence, and distribution of these scours in deep-marine systems. However, their scale and high aspect ratio mean they can be challenging to identify in outcrop. Here, we document a large-scale, composite erosion surface from the exhumed deep-marine stratigraphy of Unit 5 from the Permian Karoo Basin succession in South Africa, which is interpreted to be present at the end of a submarine channel. This study utilizes 24 sedimentary logs, 2 cored boreholes, and extensive palaeocurrent and thickness data across a 126 km2study area. Sedimentary facies analysis, thickness variations and correlation panels allowed identification of a lower heterolithic-dominated part (up to 70 m thick) and an upper sandstone-dominated part (10–40 m thick) separated by an extensive erosion surface. The lower part comprises heterolithics with abundant current and sinusoidal ripples, which due to palaeocurrents, thickness trends and adjacent depositional environments is interpreted as the aggradational lobe complex fringes. The base of the upper part comprises 2-3 medium-bedded sandstone beds interpreted as precursor lobes cut by a 3–4 km wide, 1–2 km long, and up to 28 m deep, high aspect ratio (1:100) composite scour surface. The abrupt change from heterolithics to thick-bedded sandstones marks the establishment of a new sediment delivery system, which may have been triggered by an updip channel avulsion. The composite scour and subsequent sandstone fill support a change from erosion- and bypass-dominated flows to depositional flows, which might reflect increasingly sand-rich flows as a new sediment route matured. This study provides a unique outcrop example with 3D stratigraphic control of the record of a new sediment conduit, and development and fill of a large-scale composite scour surface at a channel mouth transition zone, providing a rare insight into how scours imaged on seafloor data can be filled and preserved in the rock record.
Creep Behavior of Intact Loess Followed Unloading Paths
Authors: Li Zhenxiao , Wang Jiading , Zhang Dengfei
Published: September 2021

Several high-fill projects are carried out on the Loess Plateau, China, accompanying the progressive failure of slopes due to excavation. The compelling need requires a deep understanding of variation in the creeping behaviors of intact loess exposed to unloading. A series of creep tests of intact loess were performed under two separated unloading paths: decrease in confining pressure at constant deviator stress and decrease in confining pressure at axial stress. The results demonstrated that axial deformation followed the first unloading path always appears as compression while the three forms of axial deformation followed the second path, depending on the applied axial stress level. At a low unloading stress level, the elongation of axial deformation was observed. At a relatively unloading stress level, the axial deformation of the soil experienced the first elongation and then compression. At a high unloading stress level, the axial deformation appeared as compression, and finally, failure occurred with the increase of the unloading stress level. The failure approach index was introduced to use as the criterion for the loess to transform from stable to accelerated creeping. Finally, a modified Burgers model was proposed to characterize the creeping behavior of intact loess followed unloading paths. There was a good comparison between the calculated and measured data of the soil that establishes the rationality and validity of the proposed model.
Measuring Cognitive Load: Are There More Valid Alternatives to Likert Rating Scales?
Authors: Ouwehand Kim , Kroef Avalon van der , Wong Jacqueline , Paas Fred
Published: September 2021

Cognitive load researchers have used varying subjective techniques based on rating scales to quantify experienced cognitive load. Although it is generally assumed that subjects can introspect on their cognitive processes and have no difficulty in assigning numerical values to the imposed cognitive load, little is known about how visual characteristics of the rating scales influence the validity of the cognitive load measure. In this study we look at validity of four subjective rating scales (within groups) differing in visual appearance by participants rating perceived difficulty and invested mental effort in response to working on simple and complex weekday problems. We used two numerical scales (the nine-point Likert scale most often used in Cognitive load theory research and a Visual Analogue Scale ranging between 0–100%) and two pictorial scales (a scale consisting of emoticons ranging from a relaxed blue-colored face to a stressed red-colored face and an “embodied” scale picturing nine depicted weights from 1–9 kg). Results suggest that numerical scales better reflect cognitive processes underlying complex problem solving while pictorial scales Underlying simple problem solving. This study adds to the discussion on the challenges to quantify cognitive load through various measurement methods and whether subtleties in measurements could influence research findings.
Dipeptidyl-Peptidase-IV Inhibitors, Imigliptin and Alogliptin, Improve Beta-Cell Function in Type 2 Diabetes
Authors: Liu Xu , Liu Yang , Liu Hongzhong , Li Haiyan , Yang Jianhong , Hu Pei , Xiao Xinhua , Liu Dongyang
Published: September 2021

Objects

Imigliptin is a novel dipeptidyl peptidase-4 inhibitor. In the present study, we aimed to evaluate the effects of imigliptin and alogliptin on insulin resistance and beta-cell function in Chinese patients with type-2 diabetes mellitus (T2DM).

Methods

A total of 37 Chinese T2DM patients were randomized to receive 25 mg imigliptin, 50 mg imigliptin, placebo, and 25 mg alogliptin (positive drug) for 13 days. Oral glucose tolerance tests were conducted at baseline and on day 13, followed by the oral minimal model (OMM).

Results

Imigliptin or alogliptin treatment, compared with their baseline or placebo, was associated with higher beta-cell function parameters (φs and φtot) and lower glucose area under the curve (AUC) and postprandial glucose levels. The changes in the AUC for the glucose appearance rate between 0 and 120 min also showed a decrease in imigliptin or alogliptin groups. However, the insulin resistance parameter, fasting glucose, was not changed. For the homeostatic model assessment (HOMA-β and HOMA-IR) parameters or secretory units of islets in transplantation index (SUIT), no statistically significant changes were found both within treatments and between treatments.

Conclusions

After 13 days of treatment, imigliptin and alogliptin could decrease glycemic levels by improving beta-cell function. By comparing OMM with HOMA or SUIT results, glucose stimulation might be more sensitive for detecting changes in beta-cell function.
Weighted Gene Co-Expression Network Analysis Identifies ANGPTL4 as a Key Regulator in Diabetic Cardiomyopathy via FAK/SIRT3/ROS Pathway in Cardiomyocyte
Authors: Dai Lei , Xie Yang , Zhang Wenjun , Zhong Xiaodan , Wang Mengwen , Jiang Hongcheng , He Zhen , Liu Xiaolei , Zeng Hesong , Wang Hongjie
Published: September 2021

Background

Diabetic cardiomyopathy (DbCM) is characterized by initial impairment of left ventricular relaxation followed by contractile dysfunction. Despite intensive research, the exact mechanism remains so far unsolved.

Methods

We constructed weighted gene co-expression network analysis (WGCNA) to screen gene modules that were closely related with DbCM based on the GSE5606 dataset, which contained expression data of the cardiac left ventricle in a rodent model of streptozotocin (STZ)-induced DbCM. Then, the most related hub gene, angiopoietin-like 4 (ANGPTL4), was selected for functional ex vivo and in vitro assays. In our experiments, STZ-induced diabetic mice (C57BL/6J) and human cardiomyocytes (AC16) were used to study the functional roles and potential mechanisms of ANGPTL4 in DbCM.

Results

WGCNA analysis revealed the yellow and green modules were most correlated with DbCM, and identified ANGPTL4 as one of the most significantly upregulated hub genes (ANGPTL4, ACOT1, DECR1, HMGCS2, and PDK4). Consistent with the bioinformatic analysis, the amount of ANGPTL4 was significantly upregulated in diabetic mouse heart. DbCM group, compared with the control group, had increased phosphorylation of focal adhesion kinase (FAK), reduced SIRT3 expression, increased SOD2 acetylation, upregulated NADPH oxidase activation, elevated reactive oxygen species (ROS) produciton, and enhanced apoptosis in the diabetic mouse heart. Moreover, ANGPTL4 induced apoptosis via FAK/SIRT3/ROS pathway in human cardiomyocytes (AC16) under high glucose condition in vitro.These effects were abrogated by treatment of two independent siRNA for ANGPTL4, whereas exogenous recombinant ANGPLT4 protein treatment exacerbated those effects in AC16.

Conclusion

We found ANGPTL4, ACOT1, DECR1, HMGCS2, and PDK4 were significantly increased in diabetic heart. ANGPTL4 could promote cardiac apoptosis via a FAK/SIRT3/ROS dependent signaling pathway in DbCM.
Identification of Isocitrate Dehydrogenase 2 (IDH2) Mutation in Carotid Body Paraganglioma
Authors: Lang Fengchao , Jha Abhishek , Meuter Leah , Pacak Karel , Yang Chunzhang
Published: September 2021

Carotid body paragangliomas (PGLs) are rare neuroendocrine tumors that develop within the adventitia of the medial aspect of the carotid bifurcation. Carotid body PGLs comprise about 65% of head and neck paragangliomas, however, their genetic background remains elusive. In the present study, we report one case of carotid body PGL with a somatic mutation in the gene encoding isocitrate dehydrogenase 2 (IDH2). The missense mutation in IDH2 resulted in R172G amino acid substitution, which exhibits neomorphic activity and production of D-2-hydroxyglutarate.
The Effect of Heterogeneity on the Distribution and Treatment of PFAS in a Complex Geologic Environment
Authors: McGregor Rick , Benevenuto Leticia
Published: September 2021

Per-and polyfluoroalkyl substances (PFAS) have been identified as emerging contaminants of concern in the environment in a wide variety of media including groundwater. Typically, PFAS-impacted groundwater is extracted by pump and treat systems and treated using sorptive media such as activated carbon and ion exchange resin. Pump and treat systems are generally considered ineffective for the remediation of dissolved phase contaminants including PFAS but instead are considered applicable for plume containment. An alternative to pump and treat is in-situ treatment. The demonstrated use of in-situ treatment for PFAS-impacted groundwater is limited with only colloidal activated carbon (CAC) being shown to effectively attenuate PFAS over short and moderate time periods. Active research topics for the in-situ treatment of PFAS include the effect of heterogeneity on the distribution of the CAC, the lifespan of the CAC itself, the effect of competitive adsorption/absorption, and the effect of other geochemical conditions on the removal process. This study looked at the effect of heterogeneity on the distribution of CAC and subsequent treatment of PFAS at a site with a multiple aquifer system. The site’s geology varied from a silty sand to sand to fractured bedrock with all three units being impacted by PFAS and benzene (B), toluene (T), ethylbenzene (E), and xylene (X). Parameters evaluated included the distribution of the CAC as well as the subsequent treatment of the PFAS and BTEX. Results of groundwater sampling indicated that the PFAS detected within the groundwater were treated effectively to below their respective reporting limits for the duration of the 1-year test in both the silty sand and sand aquifers. The PFAS in the fractured rock aquifer showed a different treatment profile with longer carbon chained PFAS being attenuated preferentially compared to the shorter carbon chained PFAS. These results suggest that competitive sorptive reactions were occurring on the CAC within the fractured rock. Analysis of the unconsolidated aquifer materials determined that direct push injection of the CAC was effective at delivering the CAC to the target injection zones with post-injection total organic carbon (TOC) concentrations increasing by up to three orders of magnitude compared to pre-injection TOC concentrations. Heterogeneity did have an impact on the CAC distribution with higher hydraulic conductivity zones receiving more CAC mass than lower hydraulic conductivity zones.
Time-Dependent Toxicity of Tire Particles on Soil Nematodes
Authors: Kim Shin Woong , Leifheit Eva F. , Maaß Stefanie , Rillig Matthias C.
Published: September 2021

Tire-wear particles (TWPs) are being released into the environment by wearing down during car driving, and are considered an important microplastic pollution source. The chemical additive leaching from these polymer-based materials and its potential effects are likely temporally dynamic, since amounts of potentially toxic compounds can gradually increase with contact time of plastic particles with surrounding media. In the present study, we conducted soil toxicity tests using the soil nematode Caenorhabditis elegans with different soil pre-incubation (30 and 75 days) and exposure (short-term exposure, 2 days; lifetime exposure, 10 days) times. Soil pre-incubation increased toxicity of TWPs, and the effective concentrations after the pre-incubation were much lower than environmentally relevant concentrations. The lifetime of C. elegans was reduced faster in the TWP treatment groups, and the effective concentration for lifetime exposure tests were 100- to 1,000-fold lower than those of short-term exposure tests. Water-extractable metal concentrations (Cr, Cu, Ni, Pb, and Zn) in the TWP-soils showed no correlation with nominal TWP concentrations or pre-incubation times, and the incorporated metals in the TWPs may be not the main reason of toxicity in this study. Our results show that toxic effects of TWPs can be time-dependent, both in terms of the microplastic particles themselves and their interactions in the soil matrix, but also because of susceptibility of target organisms depending on developmental stage. It is vital that future works consider these aspects, since otherwise effects of microplastics and TWPs could be underestimated.
Sulfamethoxazole and Enrofloxacin Antibiotics Affect Primary Productivity of Phytoplankton in Fishery Environment
Authors: Shan Xiangbao , Shi Yulu , Fang Longxiang , Gui Yuan , Xing Luchang , Qiu Liping , Hu Gengdong , Chen Jiazhang
Published: September 2021

The antibiotics sulfamethoxazole (SMZ) and enrofloxacin (ENF) are commonly used in aquaculture in China, but their effects on the primary productivity of phytoplankton are unclear. On the basis of the fishery drug use standards (SMZ, 100 mg kg−1 d−1; ENF, 15 mg kg−1 d−1), these antibiotics were put into culture ponds to observe their effects on the phytoplankton community and primary productivity. The results showed that the changes in phytoplankton species at SMZ and ENF sites were different. At the ENF sites, Bacillariophyta species increased from 7 to 9, euglenophyta from 8 to 12 and cyanophyta from 11 to 9. Chlorophyta species at the SMZ sites increased from 10 to 15 and euglenophyta from 7 to 4. SMZ and ENF significantly promoted the number of cyanophyta (p < 0.05). The promoting effect of SMZ was more obvious than that of ENF. SMZ was more effective than ENF in promoting cyanophyta. The maximum number of cyanophyta at SMZ sites was 52.39 million L−1, and the concentration of SMZ was positively correlated with the number of cyanophyta. The maximum number of cyanophyta at ENF sites was 33.13 million L−1, and the promoting effect of low concentrations was more significant than that of high concentrations. Both SMZ and ENF promoted increased phytoplankton biomass, consistent with the residual time of the antibiotics in the aquaculture environment. The greatest biomass at the SMZ sites was 129.31 g m−³, and that at the ENF sites was 117.85 g m−³. The changes in the α diversity index showed that both SMZ and ENF led to a decrease in phytoplankton biodiversity, and that SMZ was more harmful to it. There were significant differences in the Shannon–Wiener, Pielou and Simpson indexes of the SMZ sites within groups (p < 0.05). The β diversity index showed that both antibiotics could change the phytoplankton habitat, but the effect of ENF on the habitat was recoverable, while that of SMZ prevented its restoration. These data will be valuable in protecting the ecological environment of fisheries and ensuring the safety and stability of fishery aquatic ecosystems.
Effects of Low-Level Artificial Light at Night on Kentucky Bluegrass and an Introduced Herbivore
Authors: Crump Morgan C. , Brown Cassandra , Griffin-Nolan Robert J. , Angeloni Lisa , Lemoine Nathan P. , Seymoure Brett M.
Published: September 2021

Increasing evidence suggests that artificial light at night (ALAN) can negatively impact organisms. However, most studies examine the impacts of ALAN on a single species or under high levels of artificial light that are infrequent or unrealistic in urban environments. We currently have little information on how low levels of artificial light emanating from urban skyglow affect plants and their interactions with herbivores. We examined how short-term, low levels of ALAN affect grass and insects, including growth rate, photosynthesis, and stomatal conductance in grass, and foraging behavior and survival in crickets. We compared growth and leaf-level gas exchange of Kentucky Bluegrass (Poa pratensis) under low-levels of ALAN (0.3 lux) and starlight conditions (0.001 lux). Furthermore, each light treatment was divided into treatments with and without house crickets (Acheta domesticus). Without crickets present, bluegrass grown under ALAN for three weeks grew taller than plants grown under natural night light levels. In the fourth week when crickets were introduced, grass height decreased resulting in no measurable effects of light treatment. There were no measurable differences in grass physiology among treatments. Our results indicate that low levels of light resulting from skyglow affect plant growth initially. However, with herbivory, the effects of ALAN on grass may be inconsequential. Gaining an understanding of how ALAN affects plant-insect interactions is critical to predicting the ecological and evolutionary consequences of anthropogenic light pollution.
The Gene-Drug Duality: Exploring the Pharmacogenomics of Indigenous Populations
Authors: Nagaraj Shivashankar H. , Toombs Maree
Published: September 2021

While pharmacogenomic studies have facilitated the rapid expansion of personalized medicine, the benefits of these findings have not been evenly distributed. Genomic datasets pertaining to Indigenous populations are sorely lacking, leaving members of these communities at a higher risk of adverse drug reactions (ADRs), and associated negative outcomes. Australia has one of the largest Indigenous populations in the world. Pharmacogenomic studies of these diverse Indigenous Australian populations have been hampered by a paucity of data. In this article, we discuss the history of pharmacogenomics and highlight the inequalities that must be addressed to ensure equal access to pharmacogenomic-based healthcare. We also review efforts to conduct the pharmacogenomic profiling of chronic diseases among Australian Indigenous populations and survey the impact of the lack of drug safety-related information on potential ADRs among individuals in these communities.
Upregulation of Linc00284 Promotes Lung Cancer Progression by Regulating the miR-205-3p/c-Met Axis
Authors: Sheng Wang , Guo Weixi , Lu Fang , Liu Hongming , Xia Rongmu , Dong Feng
Published: September 2021

Lung cancer (LC) is a malignant tumor with the highest incidence and mortality rates worldwide. Linc00284, a long non-coding RNA, is a newly discovered regulator of LC. This study aimed to explore the role of Linc00284 in LC progression. Gene expression levels were detected by RT-qPCR and/or western blot analysis. Cell migratory and invasive capabilities were measured by wound healing and transwell assays. Subcutaneous xenograft models were constructed to examine tumor growth of LC cells. Data showed that Linc00284 was significantly upregulated in LC tissues compared to adjacent normal lung tissues and predicted poor prognosis in patients with LC. In vitro, Linc00284 was highly expressed in LC cells and was mainly localized in the cytoplasm. Mechanistically, Linc00284 directly bound to miR-205-3p, leading to the upregulation of c-Met expression. A significant negative correlation was observed between Linc00284 and miR-205-3p expression levels, and the Linc00284 level was positively correlated with the c-Met expression. Linc00284/miR-205-3p/c-Met regulatory axis promotes LC cell proliferation, migration, and invasion. Furthermore, the in vivo results indicated that Linc00284 knockdown markedly suppressed tumor growth. Taken together, these data suggest that Linc00284 facilitates LC progression by targeting the miR-205-3p/c-Met axis, which may be a potential target for LC treatment.
Trio-Based Low-Pass Genome Sequencing Reveals Characteristics and Significance of Rare Copy Number Variants in Prenatal Diagnosis
Authors: Chau Matthew Hoi Kin , Qian Jicheng , Chen Zihan , Li Ying , Zheng Yu , Tse Wing Ting , Kwok Yvonne K. , Leung Tak Yeung , Dong Zirui , Choy Kwong Wai
Published: September 2021

Background: Low-pass genome sequencing (GS) detects clinically significant copy number variants (CNVs) in prenatal diagnosis. However, detection at improved resolutions leads to an increase in the number of CNVs identified, increasing the difficulty of clinical interpretation and management.

Methods: Trio-based low-pass GS was performed in 315 pregnancies undergoing invasive testing. Rare CNVs detected in the fetuses were investigated. The characteristics of rare CNVs were described and compared to curated CNVs in other studies.

Results: A total of 603 rare CNVs, namely, 597 constitutional and 6 mosaic CNVs, were detected in 272 fetuses (272/315, 86.3%), providing 1.9 rare CNVs per fetus (603/315). Most CNVs were smaller than 1 Mb (562/603, 93.2%), while 1% (6/603) were mosaic. Forty-six de novo (7.6%, 46/603) CNVs were detected in 11.4% (36/315) of the cases. Eighty-four CNVs (74 fetuses, 23.5%) involved disease-causing genes of which the mode of inheritance was crucial for interpretation and assessment of recurrence risk. Overall, 31 pathogenic/likely pathogenic CNVs were detected, among which 25.8% (8/31) were small (<100 kb; n = 3) or mosaic CNVs (n = 5).

Conclusion: We examined the landscape of rare CNVs with parental inheritance assignment and demonstrated that they occur frequently in prenatal diagnosis. This information has clinical implications regarding genetic counseling and consideration for trio-based CNV analysis.