bluuebunny/crossref_metadata_2025 huggingface dataset:
ZFYVE28 mediates insulin resistance by promoting phosphorylated insulin receptor degradation via increasing late endosomes production
Authors: Yu Liang , Xu Mengchen , Yan Yupeng , Huang Shuchen , Yuan Mengmeng , Cui Bing , Lv Cheng , Zhang Yu , Wang Hongrui , Jin Xiaolei , Hui Rutai , Wang Yibo
Published: October 2023

Insulin resistance is associated with many pathological conditions, and an in-depth understanding of the mechanisms involved is necessary to improve insulin sensitivity. Here, we show that ZFYVE28 expression is decreased in insulin-sensitive obese individuals but increased in insulin-resistant individuals. Insulin signaling inhibits ZFYVE28 expression by inhibiting NOTCH1 via the RAS/ERK pathway, whereas ZFYVE28 expression is elevated due to impaired insulin signaling in insulin resistance. While Zfyve28 overexpression impairs insulin sensitivity and causes lipid accumulation, Zfyve28 knockout in mice can significantly improve insulin sensitivity and other indicators associated with insulin resistance. Mechanistically, ZFYVE28 colocalizes with early endosomes via the FYVE domain, which inhibits the generation of recycling endosomes but promotes the conversion of early to late endosomes, ultimately promoting phosphorylated insulin receptor degradation. This effect disappears with deletion of the FYVE domain. Overall, in this study, we reveal that ZFYVE28 is involved in insulin resistance by promoting phosphorylated insulin receptor degradation, and ZFYVE28 may be a potential therapeutic target to improve insulin sensitivity.
CNS tumor stroma transcriptomics identify perivascular fibroblasts as predictors of immunotherapy resistance in glioblastoma patients
Authors: Zarodniuk Maksym , Steele Alexander , Lu Xin , Li Jun , Datta Meenal
Published: October 2023

Excessive deposition of extracellular matrix (ECM) is a hallmark of solid tumors; however, it remains poorly understood which cellular and molecular components contribute to the formation of ECM stroma in central nervous system (CNS) tumors. Here, we undertake a pan-CNS analysis of retrospective gene expression datasets to characterize inter- and intra-tumoral heterogeneity of ECM remodeling signatures in both adult and pediatric CNS disease. We find that CNS lesions – glioblastoma in particular – can be divided into two ECM-based subtypes (ECMhi and ECMlo) that are influenced by the presence of perivascular stromal cells resembling cancer-associated fibroblasts (CAFs). Ligand-receptor network analysis predicts that perivascular fibroblasts activate signaling pathways responsible for recruitment of tumor-associated macrophages and promotion of cancer stemness. Our analysis reveals that perivascular fibroblasts are correlated with unfavorable response to immune checkpoint blockade in glioblastoma and poor patient survival across a subset of CNS tumors. We provide insights into new stroma-driven mechanisms underlying immune evasion and immunotherapy resistance in CNS tumors like glioblastoma, and discuss how targeting these perivascular fibroblasts may prove an effective approach to improving treatment response and patient survival in a variety of CNS tumors.
Benchmarking quantum logic operations relative to thresholds for fault tolerance
Authors: Hashim Akel , Seritan Stefan , Proctor Timothy , Rudinger Kenneth , Goss Noah , Naik Ravi K. , Kreikebaum John Mark , Santiago David I. , Siddiqi Irfan
Published: October 2023

Contemporary methods for benchmarking noisy quantum processors typically measure average error rates or process infidelities. However, thresholds for fault-tolerant quantum error correction are given in terms of worst-case error rates—defined via the diamond norm—which can differ from average error rates by orders of magnitude. One method for resolving this discrepancy is to randomize the physical implementation of quantum gates, using techniques like randomized compiling (RC). In this work, we use gate set tomography to perform precision characterization of a set of two-qubit logic gates to study RC on a superconducting quantum processor. We find that, under RC, gate errors are accurately described by a stochastic Pauli noise model without coherent errors, and that spatially correlated coherent errors and non-Markovian errors are strongly suppressed. We further show that the average and worst-case error rates are equal for randomly compiled gates, and measure a maximum worst-case error of 0.0197(3) for our gate set. Our results show that randomized benchmarks are a viable route to both verifying that a quantum processor’s error rates are below a fault-tolerance threshold, and to bounding the failure rates of near-term algorithms, if—and only if—gates are implemented via randomization methods which tailor noise.
The modular biochemical reaction network structure of cellular translation
Authors: Cuevas-Zuviría Bruno , Fer Evrim , Adam Zachary R. , Kaçar Betül
Published: October 2023

Translation is an essential attribute of all living cells. At the heart of cellular operation, it is a chemical information decoding process that begins with an input string of nucleotides and ends with the synthesis of a specific output string of peptides. The translation process is interconnected with gene expression, physiological regulation, transcription, and responses to signaling molecules, among other cellular functions. Foundational efforts have uncovered a wealth of knowledge about the mechanistic functions of the components of translation and their many interactions between them, but the broader biochemical connections between translation, metabolism and polymer biosynthesis that enable translation to occur have not been comprehensively mapped. Here we present a multilayer graph of biochemical reactions describing the translation, polymer biosynthesis and metabolism networks of an Escherichia coli cell. Intriguingly, the compounds that compose these three layers are distinctly aggregated into three modes regardless of their layer categorization. Multimodal mass distributions are well-known in ecosystems, but this is the first such distribution reported at the biochemical level. The degree distributions of the translation and metabolic networks are each likely to be heavy-tailed, but the polymer biosynthesis network is not. A multimodal mass-degree distribution indicates that the translation and metabolism networks are each distinct, adaptive biochemical modules, and that the gaps between the modes reflect evolved responses to the functional use of metabolite, polypeptide and polynucleotide compounds. The chemical reaction network of cellular translation opens new avenues for exploring complex adaptive phenomena such as percolation and phase changes in biochemical contexts.
Genetics re-establish the utility of 2-methylhopanes as cyanobacterial biomarkers before 750 million years ago
Authors: Hoshino Yosuke , Nettersheim Benjamin J. , Gold David A. , Hallmann Christian , Vinnichenko Galina , van Maldegem Lennart M. , Bishop Caleb , Brocks Jochen J. , Gaucher Eric A.
Published: October 2023

Fossilized lipids offer a rare glimpse into ancient ecosystems. 2-Methylhopanes in sedimentary rocks were once used to infer the importance of cyanobacteria as primary producers throughout geological history. However, the discovery of hopanoid C-2 methyltransferase (HpnP) in Alphaproteobacteria led to the downfall of this molecular proxy. In the present study, we re-examined the distribution of HpnP in a new phylogenetic framework including recently proposed candidate phyla and re-interpreted a revised geological record of 2-methylhopanes based on contamination-free samples. We show that HpnP was probably present in the last common ancestor of cyanobacteria, while the gene appeared in Alphaproteobacteria only around 750 million years ago (Ma). A subsequent rise of sedimentary 2-methylhopanes around 600 Ma probably reflects the expansion of Alphaproteobacteria that coincided with the rise of eukaryotic algae—possibly connected by algal dependency on microbially produced vitamin B12. Our findings re-establish 2-methylhopanes as cyanobacterial biomarkers before 750 Ma and thus as a potential tool to measure the importance of oxygenic cyanobacteria as primary producers on early Earth. Our study illustrates how genetics can improve the diagnostic value of biomarkers and refine the reconstruction of early ecosystems.
Stunting in infancy is associated with atypical activation of working memory and attention networks
Authors: Wijeakumar Sobanawartiny , Forbes Samuel H. , Magnotta Vincent A. , Deoni Sean , Jackson Kiara , Singh Vinay P. , Tiwari Madhuri , Kumar Aarti , Spencer John P.
Published: October 2023

Stunting is associated with poor long-term cognitive, academic and economic outcomes, yet the mechanisms through which stunting impacts cognition in early development remain unknown. In a first-ever neuroimaging study conducted on infants from rural India, we demonstrate that stunting impacts a critical, early-developing cognitive system—visual working memory. Stunted infants showed poor visual working memory performance and were easily distractible. Poor performance was associated with reduced engagement of the left anterior intraparietal sulcus, a region involved in visual working memory maintenance and greater suppression in the right temporoparietal junction, a region involved in attentional shifting. When assessed one year later, stunted infants had lower problem-solving scores, while infants of normal height with greater left anterior intraparietal sulcus activation showed higher problem-solving scores. Finally, short-for-age infants with poor physical growth indices but good visual working memory performance showed more positive outcomes suggesting that intervention efforts should focus on improving working memory and reducing distractibility in infancy.
DNA-binding protein PfAP2-P regulates parasite pathogenesis during malaria parasite blood stages
Authors: Subudhi Amit Kumar , Green Judith L. , Satyam Rohit , Salunke Rahul P. , Lenz Todd , Shuaib Muhammad , Isaioglou Ioannis , Abel Steven , Gupta Mohit , Esau Luke , Mourier Tobias , Nugmanova Raushan , Mfarrej Sara , Shivapurkar Rupali , Stead Zenaida , Rached Fathia Ben , Ostwal Yogesh , Sougrat Rachid , Dada Ashraf , Kadamany Abdullah Fuaad , Fischle Wolfgang , Merzaban Jasmeen , Knuepfer Ellen , Ferguson David J. P. , Gupta Ishaan , Le Roch Karine G. , Holder Anthony A. , Pain Arnab
Published: October 2023

Malaria-associated pathogenesis such as parasite invasion, egress, host cell remodelling and antigenic variation requires concerted action by many proteins, but the molecular regulation is poorly understood. Here we have characterized an essential Plasmodium-specific Apicomplexan AP2 transcription factor in Plasmodium falciparum (PfAP2-P; pathogenesis) during the blood-stage development with two peaks of expression. An inducible knockout of gene function showed that PfAP2-P is essential for trophozoite development, and critical for var gene regulation, merozoite development and parasite egress. Chromatin immunoprecipitation sequencing data collected at timepoints matching the two peaks of pfap2-p expression demonstrate PfAP2-P binding to promoters of genes controlling trophozoite development, host cell remodelling, antigenic variation and pathogenicity. Single-cell RNA sequencing and fluorescence-activated cell sorting revealed de-repression of most var genes in Δpfap2-p parasites. Δpfap2-p parasites also overexpress early gametocyte marker genes, indicating a regulatory role in sexual stage conversion. We conclude that PfAP2-P is an essential upstream transcriptional regulator at two distinct stages of the intra-erythrocytic development cycle.
Effects of psoriasis and psoralen exposure on the somatic mutation landscape of the skin
Authors: Olafsson Sigurgeir , Rodriguez Elke , Lawson Andrew R. J. , Abascal Federico , Huber Axel Rosendahl , Suembuel Melike , Jones Philip H. , Gerdes Sascha , Martincorena Iñigo , Weidinger Stephan , Campbell Peter J. , Anderson Carl A.
Published: October 2023

Somatic mutations are hypothesized to play a role in many non-neoplastic diseases. We performed whole-exome sequencing of 1,182 microbiopsies dissected from lesional and nonlesional epidermis from 111 patients with psoriasis to search for evidence that somatic mutations in keratinocytes may influence the disease process. Lesional skin remained highly polyclonal, showing no evidence of large-scale spread of clones carrying potentially pathogenic mutations. The mutation rate of keratinocytes was similarly only modestly affected by the disease. We found evidence of positive selection in previously reported driver genes NOTCH1, NOTCH2, TP53, FAT1 and PPM1D and also identified mutations in four genes (GXYLT1, CHEK2, ZFP36L2 and EEF1A1) that we hypothesize are selected for in squamous epithelium irrespective of disease status. Finally, we describe a mutational signature of psoralens—a class of chemicals previously found in some sunscreens and which are used as part of PUVA (psoralens and ultraviolet-A) photochemotherapy treatment for psoriasis.
Lineage specific extracellular vesicle-associated protein biomarkers for the early detection of high grade serous ovarian cancer
Authors: Trinidad Camille V. , Pathak Harsh B. , Cheng Shibo , Tzeng Shin-Cheng , Madan Rashna , Sardiu Mihaela E. , Bantis Leonidas E. , Deighan Clayton , Jewell Andrea , Rayamajhi Sagar , Zeng Yong , Godwin Andrew K.
Published: October 2023

High grade serous ovarian carcinoma (HGSOC) accounts for ~ 70% of ovarian cancer cases. Non-invasive, highly specific blood-based tests for pre-symptomatic screening in women are crucial to reducing the mortality associated with this disease. Since most HGSOCs typically arise from the fallopian tubes (FT), our biomarker search focused on proteins found on the surface of extracellular vesicles (EVs) released by both FT and HGSOC tissue explants and representative cell lines. Using mass spectrometry, 985 EV proteins (exo-proteins) were identified that comprised the FT/HGSOC EV core proteome. Transmembrane exo-proteins were prioritized because these could serve as antigens for capture and/or detection. With a nano-engineered microfluidic platform, six newly discovered exo-proteins (ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, MYOF) plus a known HGSOC associated protein, FOLR1 exhibited classification performance ranging from 85 to 98% in a case–control study using plasma samples representative of early (including stage IA/B) and late stage (stage III) HGSOCs. Furthermore, by a linear combination of IGSF8 and ITGA5 based on logistic regression analysis, we achieved a sensitivity of 80% with 99.8% specificity and a positive predictive value of 13.8%. Importantly, these exo-proteins also can accurately discriminate between ovarian and 12 types of cancers commonly diagnosed in women. Our studies demonstrate that these lineage-associated exo-biomarkers can detect ovarian cancer with high specificity and sensitivity early and potentially while localized to the FT when patient outcomes are more favorable.
Comparing extraction method efficiency for high-throughput palaeoproteomic bone species identification
Authors: Mylopotamitaki Dorothea , Harking Florian S. , Taurozzi Alberto J. , Fagernäs Zandra , Godinho Ricardo M. , Smith Geoff M. , Weiss Marcel , Schüler Tim , McPherron Shannon P. , Meller Harald , Cascalheira João , Bicho Nuno , Olsen Jesper V. , Hublin Jean-Jacques , Welker Frido
Published: October 2023

High-throughput proteomic analysis of archaeological skeletal remains provides information about past fauna community compositions and species dispersals in time and space. Archaeological skeletal remains are a finite resource, however, and therefore it becomes relevant to optimize methods of skeletal proteome extraction. Ancient proteins in bone specimens can be highly degraded and consequently, extraction methods for well-preserved or modern bone might be unsuitable for the processing of highly degraded skeletal proteomes. In this study, we compared six proteomic extraction methods on Late Pleistocene remains with variable levels of proteome preservation. We tested the accuracy of species identification, protein sequence coverage, deamidation, and the number of post-translational modifications per method. We find striking differences in obtained proteome complexity and sequence coverage, highlighting that simple acid-insoluble proteome extraction methods perform better in highly degraded contexts. For well-preserved specimens, the approach using EDTA demineralization and protease-mix proteolysis yielded a higher number of identified peptides. The protocols presented here allowed protein extraction from ancient bone with a minimum number of working steps and equipment and yielded protein extracts within three working days. We expect further development along this route to benefit large-scale screening applications of relevance to archaeological and human evolution research.
Pan-cancer analysis revealing that PTPN2 is an indicator of risk stratification for acute myeloid leukemia
Authors: Wang Xuanyu , Wu Sanyun , Sun Le , Jin Peipei , Zhang Jianmin , Liu Wen , Zhan Zhuo , Wang Zisong , Liu Xiaoping , He Li
Published: October 2023

The non-receptor protein tyrosine phosphatases gene family (PTPNs) is involved in the tumorigenesis and development of many cancers, but the role of PTPNs in acute myeloid leukemia (AML) remains unclear. After a comprehensive evaluation on the expression patterns and immunological effects of PTPNs using a pan-cancer analysis based on RNA sequencing data obtained from The Cancer Genome Atlas, the most valuable gene PTPN2 was discovered. Further investigation of the expression patterns of PTPN2 in different tissues and cells showed a robust correlation with AML. PTPN2 was then systematically correlated with immunological signatures in the AML tumor microenvironment and its differential expression was verified using clinical samples. In addition, a prediction model, being validated and compared with other models, was developed in our research. The systematic analysis of PTPN family reveals that the effect of PTPNs on cancer may be correlated to mediating cell cycle-related pathways. It was then found that PTPN2 was highly expressed in hematologic diseases and bone marrow tissues, and its differential expression in AML patients and normal humans was verified by clinical samples. Based on its correlation with immune infiltrates, immunomodulators, and immune checkpoint, PTPN2 was found to be a reliable biomarker in the immunotherapy cohort and a prognostic predictor of AML. And PTPN2'riskscore can accurately predict the prognosis and response of cancer immunotherapy. These findings revealed the correlation between PTPNs and immunophenotype, which may be related to cell cycle. PTPN2 was differentially expressed between clinical AML patients and normal people. It is a diagnostic biomarker and potentially therapeutic target, providing targeted guidance for clinical treatment.
Excitatory purinergic and cholinergic expression changed in a partial bladder outlet obstruction-induced overactive bladder rat model
Authors: Huang Jingyi , Li Hongliang , Zhang Yao , Liu Jiaye , Cao Hongying , Long Yongling
Published: October 2023

Overactive bladder (OAB) is a common, long-term symptom complex with a high prevalence in women worldwide. OAB has caused a social burden, and effective treatments are urgently needed. However, the pathogenesis of OAB has yet to be elucidated. Model rats underwent bladder outlet obstruction surgery. In the 2nd, 3rd, and 4th weeks after surgery, metabolic cages were used to detect the 12 h urine volume of rats in the sham and model groups. The urodynamic parameters bladder leak point pressure (BPLL), maximum voiding pressure (MVP), residual volume (RV), maximum bladder capacity (MBC), bladder compliance (BC), voided efficiency (VE), and non-voiding contractions (NVCs) were also detected. Moreover, the contractile responses of isolated detrusor muscles to electrical and carbachol stimulation were examined at the abovementioned time points. At the 4th week after surgery, the bladders of both groups were obtained for hematoxylin–eosin (H&E) and Masson’s trichrome staining. Real-time qPCR and Western blot were performed to quantify the expression of choline acetyltransferase (ChAT) and solute carrier family 17 member 9 (SLC17A9). At week 4, compared with the sham group, the 12 h urine volume of PBOO group increased significantly. The BLPP, MVP, VE, MBC, and NVCs increased significantly, and the VE was significantly reduced in 4-week PBOO group. The contractile responses of isolated detrusor muscles to electrical and carbachol stimulation significantly increased in 4-week PBOO group. In the 4-week PBOO group, the bladder wall and the ratio of bladder muscle to collagen within the bladder smooth muscle layer wall were significantly higher than those in the sham group. ChAT and SLC17A9 mRNA and protein expression in the OAB model rats significantly increased. At 4 weeks after PBOO, the OAB model was successfully established. The gene and protein expression levels of ChAT and SLC17A9 increased in the bladder of the OAB model, suggesting that OAB may be related to increased excitatory purinergic and cholinergic expression.
Comparison between an SGLT2 inhibitor and insulin in tumor-to-tissue contrasts in 18F-FDG PET imaging of diabetic mice
Authors: Meidai Liang , Yujing Du , Zhaoyu Liu , Shanshi Li , Guangyu Zhao , Yan Fan , Xiuying Yang , Jianhua Zhang
Published: October 2023

18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) has been widely utilized for tumor diagnosis. Hyperglycemia affects the 18F-FDG uptake and reduces tumor-to-tissue contrasts, however, ideal hypoglycemic drugs are lacking. This study compared the role of insulin with the novel widely used hypoglycemic drug, sodium-glucose cotransporter 2 (SGLT2) inhibitor, on 18F-FDG PET imaging in diabetic conditions. The streptozotocin (STZ)-induced diabetic C57BL/6N mice were inoculated with B16 (mouse melanoma) cells to establish the xenograft tumor model. After the mice had been administrated with dapagliflozin (30 mg/kg, IG) or insulin (0.75 U/kg, IP) for one hour, 9.25 MBq/10 g 18F-FDG was injected. Biodistributions were detected by gamma counting and microPET imaging. The results showed dapagliflozin did not significantly affect the 18F-FDG uptake in tumors but reduced uptake in reference tissues, resulting in a significant increase in the tumor-to-skeletal muscle ratio. Conversely, insulin increased 18F-FDG uptake in tumors without significant reduction in uptake in reference tissues; Although there was an observable improvement in tumor imaging, it did not reach significantly statistical differences. This study suggests that insulin and SGLT2 inhibitor yield comparable effects on the quality of 18F-FDG PET imaging in diabetic patients. Nevertheless, SGLT2 inhibitors would be more suitable when skeletal muscle is used as reference tissue.
Comparative analysis between 2D and 3D colorectal cancer culture models for insights into cellular morphological and transcriptomic variations
Authors: Abbas Zaid Nsaif , Al-Saffar Ali Z. , Jasim Saba Mahdi , Sulaiman Ghassan M.
Published: October 2023

Drug development is a time-consuming and expensive process, given the low success rate of clinical trials. Now, anticancer drug developments have shifted to three-dimensional (3D) models which are more likely to mimic tumor behavior compared to traditional two-dimensional (2D) cultures. A comparative study among different aspects was conducted between 2D and 3D cultures using colorectal cancer (CRC) cell lines, in addition, Formalin-Fixed Paraffin-Embedded (FFPE) block samples of patients with CRC were used for evaluation. Compared to the 2D culture, cells grown in 3D displayed significant (p < 0.01) differences in the pattern of cell proliferation over time, cell death phase profile, expression of tumorgenicity-related genes, and responsiveness to 5-fluorouracil, cisplatin, and doxorubicin. Epigenetically, 3D cultures and FFPE shared the same methylation pattern and microRNA expression, while 2D cells showed elevation in methylation rate and altered microRNA expression. Lastly, transcriptomic study depending on RNA sequencing and thorough bioinformatic analyses showed significant (p-adj < 0.05) dissimilarity in gene expression profile between 2D and 3D cultures involving thousands of genes (up/down-regulated) of multiple pathways for each cell line. Taken together, the study provides insights into variations in cellular morphologies between cells cultured in 2D and 3D models.
A text mining approach to categorize patient safety event reports by medication error type
Authors: Boxley Christian , Fujimoto Mari , Ratwani Raj M. , Fong Allan
Published: October 2023

Patient safety reporting systems give healthcare provider staff the ability to report medication related safety events and errors; however, many of these reports go unanalyzed and safety hazards go undetected. The objective of this study is to examine whether natural language processing can be used to better categorize medication related patient safety event reports. 3,861 medication related patient safety event reports that were previously annotated using a consolidated medication error taxonomy were used to develop three models using the following algorithms: (1) logistic regression, (2) elastic net, and (3) XGBoost. After development, models were tested, and model performance was analyzed. We found the XGBoost model performed best across all medication error categories. ‘Wrong Drug’, ‘Wrong Dosage Form or Technique or Route’, and ‘Improper Dose/Dose Omission’ categories performed best across the three models. In addition, we identified five words most closely associated with each medication error category and which medication error categories were most likely to co-occur. Machine learning techniques offer a semi-automated method for identifying specific medication error types from the free text of patient safety event reports. These algorithms have the potential to improve the categorization of medication related patient safety event reports which may lead to better identification of important medication safety patterns and trends.
A quantitative method for determination of colistin E2 methanesulphonate in human plasma by 15N-labeled colistin E2
Authors: Xu Hongjiang , Li Yanan , Zhang Jing , Zhang Jinhua , Lu Jianguang , Zhang Xiquan , Yang Ling , Zhao Wenjie , Feng Jun
Published: October 2023

The single-component colistin E2, with superior antibacterial activity and lower toxicity, was being developed as the latest generation of polymyxin drugs. However, colistin E2 has not been tested quantitatively in biological matrices. In this study, based on the quantitative detection of colistin methanesulphonate (CMS) and colistin by Zhao et al., 15N-labeled colistin E2 was used as an internal standard (IS) for a more accurate quantitative detection of CMS E2 in human plasma. A rapid ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC–MS/MS) assay method was developed for determination of CMS E2 and colistin E2 in human plasma. After pretreatment of plasma samples by 96-well SPE Supra-Clean Weak Cation Exchange (WCX) plate, the formed colistin E2 was detected and quantified by UHPLC–MS/MS system. All plasma lots were found to be free of interferences with the analyte. The matrix has no effect on the quantitation of the analyte. No significant effect of the carryover was observed. The dilution integrity was demonstrated in plasma samples without the loss of accuracy and precision. The lower limit of quantification (LLOQ) was 0.0300 mg/L for colistin E2 in plasma with accuracy (relative error, 5.1–12.7%) and precision (relative standard deviation,  − 5.7–9.3%). Stability of CMS E2 and colistin E2 was demonstrated in biological samples before and during sample treatment, and in the extract. Furthermore, this method was successfully applied to the analysis of plasma samples obtained from Chinese healthy volunteers receiving a single intravenous CMS E2 dose of 5 mg/kg. In conclusion, the detection method was characterized by speed and high accuracy, which laid a solid foundation for the subsequent development of CMS E2 drug.
A pill as a quick solution: association between painkiller intake, empathy, and prosocial behavior
Authors: Banwinkler Magdalena , Rütgen Markus , Lamm Claus , Hartmann Helena
Published: October 2023

Previous research has demonstrated a link between the administration of analgesic drugs and the reduction of empathy levels in humans. This apparent blunting effect of pain medication has been explained through shared neural mechanisms for the first-hand and the empathic experience of pain (simulation theory). Considering that analgesics are among the most consumed drugs in the world and the ability to empathize with others is fundamental to human social interactions, the aim of the present study was to investigate whether the typical day-to-day analgesic consumption rate in Austria and Germany is associated with a reduction in empathy and prosocial behavior. We therefore collected self-reports of analgesic consumption behavior as well as empathy for pain and prosocial behavior measures in an online survey (n = 940). Analyses revealed no significant association between the analgesic intake frequency and measures of empathy or prosocial behavior. However, liberal intake of analgesics (i.e. mind-set of “a pill is a quick solution”) was linked to lower empathic concern and helping behavior, which may hint towards a negative effect in people who take pain medication for non-pain related issues or episodes of low pain. Nevertheless, further research is needed to investigate the effects of analgesic drugs in high frequency users.
Computational completion of the Aurora interaction region of N-Myc in the Aurora a kinase complex
Authors: Altiner Pinar , Çınaroğlu Süleyman Selim , Timucin Ahmet Can , Timucin Emel
Published: October 2023

Inhibiting protein–protein interactions of the Myc family is a viable pharmacological strategy for modulation of the levels of Myc oncoproteins in cancer. Aurora A kinase (AurA) and N-Myc interaction is one of the most attractive targets of this strategy because formation of this complex blocks proteasomal degradation of N-Myc in neuroblastoma. Two crystallization studies have captured this complex (PDB IDs: 5g1x, 7ztl), partially resolving the AurA interaction region (AIR) of N-Myc. Prompted by the missing N-Myc fragment in these crystal structures, we modeled the complete structure between AurA and N-Myc, and comprehensively analyzed how the incomplete and complete N-Myc behave in complex by molecular dynamics simulations. Molecular dynamics simulations of the incomplete PDB complex (5g1x) repeatedly showed partial dissociation of the short N-Myc fragment (61–89) from the kinase. The missing N-Myc (19–60) fragment was modeled utilizing the N-terminal lobe of AurA as the protein–protein interaction surface, wherein TPX2, a well-known partner of AurA, also binds. Binding free energy calculations along with flexibility analysis confirmed that the complete AIR of N-Myc stabilizes the complex, accentuating the N-terminal lobe of AurA as a binding site for the missing N-Myc fragment (19–60). We further generated additional models consisting of only the missing N-Myc (19–60), and the fused form of TPX2 (7–43) and N-Myc (61–89). These partners also formed more stable interactions with the N-terminal lobe of AurA than did the incomplete N-Myc fragment (61–89) in the 5g1x complex. Altogether, this study provides structural insights into the involvement of the N-terminus of the AIR of N-Myc and the N-terminal lobe of AurA in formation of a stable complex, reflecting its potential for effective targeting of N-Myc.
Identification of PCB congeners and their thresholds associated with diabetes using decision tree analysis
Authors: Lan Tuo , Liu Buyun , Bao Wei , Thorne Peter S.
Published: October 2023

Few studies have investigated the potential combined effects of multiple PCB congeners on diabetes. To address this gap, we used data from 1244 adults in the National Health and Nutrition Examination Survey (NHANES) 2003–2004. We used (1) classification trees to identify serum PCB congeners and their thresholds associated with diabetes; and (2) logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of diabetes with combined PCB congeners. Of the 40 PCB congeners examined, PCB 126 has the strongest association with diabetes. The adjusted OR of diabetes comparing PCB 126 > 0.025 to ≤ 0.025 ng/g was 2.14 (95% CI 1.30–3.53). In the subpopulation with PCB 126 > 0.025 ng/g, a lower PCB 101 concentration was associated with an increased risk of diabetes (comparing PCB 101 < 0.72 to ≥ 0.72 ng/g, OR 3.3, 95% CI 1.27–8.55). In the subpopulation with PCB 126 > 0.025 & PCB 101 < 0.72 ng/g, a higher PCB 49 concentration was associated with an increased risk of diabetes (comparing PCB 49 > 0.65 to ≤ 0.65 ng/g, OR 2.79, 95% CI 1.06–7.35). This nationally representative study provided new insights into the combined associations of PCBs with diabetes.
Videoconference fatigue from a neurophysiological perspective: experimental evidence based on electroencephalography (EEG) and electrocardiography (ECG)
Authors: Riedl René , Kostoglou Kyriaki , Wriessnegger Selina C. , Müller-Putz Gernot R.
Published: October 2023

In the recent past, many organizations and people have substituted face-to-face meetings with videoconferences. Among others, tools like Zoom, Teams, and Webex have become the “new normal” of human social interaction in many domains (e.g., business, education). However, this radical adoption and extensive use of videoconferencing tools also has a dark side, referred to as videoconference fatigue (VCF). To date only self-report evidence has shown that VCF is a serious issue. However, based on self-reports alone it is hardly possible to provide a comprehensive understanding of a cognitive phenomenon like VCF. Against this background, we examined VCF also from a neurophysiological perspective. Specifically, we collected and analyzed electroencephalography (continuous and event-related) and electrocardiography (heart rate and heart rate variability) data to investigate whether VCF can also be proven on a neurophysiological level. We conducted a laboratory experiment based on a within-subjects design (N = 35). The study context was a university lecture, which was given in a face-to-face and videoconferencing format. In essence, the neurophysiological data—together with questionnaire data that we also collected—show that 50 min videoconferencing, if compared to a face-to-face condition, results in changes in the human nervous system which, based on existing literature, can undoubtedly be interpreted as fatigue. Thus, individuals and organizations must not ignore the fatigue potential of videoconferencing. A major implication of our study is that videoconferencing should be considered as a possible complement to face-to-face interaction, but not as a substitute.
Validation and evaluation of subject-specific finite element models of the pediatric knee
Authors: Karimi Dastgerdi Ayda , Esrafilian Amir , Carty Christopher P. , Nasseri Azadeh , Yahyaiee Bavil Alireza , Barzan Martina , Korhonen Rami K. , Astori Ivan , Hall Wayne , Saxby David John
Published: October 2023

Finite element (FE) models have been widely used to investigate knee joint biomechanics. Most of these models have been developed to study adult knees, neglecting pediatric populations. In this study, an atlas-based approach was employed to develop subject-specific FE models of the knee for eight typically developing pediatric individuals. Initially, validation simulations were performed at four passive tibiofemoral joint (TFJ) flexion angles, and the resulting TFJ and patellofemoral joint (PFJ) kinematics were compared to corresponding patient-matched measurements derived from magnetic resonance imaging (MRI). A neuromusculoskeletal-(NMSK)-FE pipeline was then used to simulate knee biomechanics during stance phase of walking gait for each participant to evaluate model simulation of a common motor task. Validation simulations demonstrated minimal error and strong correlations between FE-predicted and MRI-measured TFJ and PFJ kinematics (ensemble average of root mean square errors < 5 mm for translations and < 4.1° for rotations). The FE-predicted kinematics were strongly correlated with published reports (ensemble average of Pearson's correlation coefficients (ρ) > 0.9 for translations and ρ > 0.8 for rotations), except for TFJ mediolateral translation and abduction/adduction rotation. For walking gait, NMSK-FE model-predicted knee kinematics, contact areas, and contact pressures were consistent with experimental reports from literature. The strong agreement between model predictions and experimental reports underscores the capability of sequentially linked NMSK-FE models to accurately predict pediatric knee kinematics, as well as complex contact pressure distributions across the TFJ articulations. These models hold promise as effective tools for parametric analyses, population-based clinical studies, and enhancing our understanding of various pediatric knee injury mechanisms. They also support intervention design and prediction of surgical outcomes in pediatric populations.
Dual-target drugs against Leishmania donovani for potential novel therapeutics
Authors: Bora Kushal , Sarma Manash , Kanaujia Shankar Prasad , Dubey Vikash Kumar
Published: October 2023

Antioxidant defense mechanisms are important for a parasite to overcome oxidative stress and survive within host macrophage cells. Mitochondrial iron superoxide dismutase A (FeSODA) and trypanothione reductase (TR) are critical enzymes in the antioxidant defense mechanism of Leishmania donovani. FeSODA is responsible for neutralizing reactive oxygen species in mitochondria, while TR is responsible for reducing trypanothione, the molecules that help the parasite fight oxidative stress in Leishmania. In this study, we used multitarget ligands to inhibit both the FeSODA and TR enzymes. We combined structure-based drug design using virtual screening approach to find inhibitors against both the targets. The ZINC15 database of biogenic compounds was utilized to extract drugs-like molecules against leishmaniasis. The compounds were screened by standard precision (SP) and extra precision (XP) docking methods. Two compounds, ZINC000008876351 and ZINC000253403245, were selected based on molecular docking based on the binding affinity for both the targets. The screened molecules ZINC000008876351 and ZINC000253403245 showed strong hydrogen bonding with the target proteins according to the Molecular mechanics with generalised Born and surface area solvation (MM-GBSA) techniques. These two compounds were also experimentally investigated on promastigotes stage of L. donovani. Under in vitro condition, the compounds show inhibitory effects on L. donovani promastigotes with IC50 values of 24.82 ± 0.61 µM for ZINC000008876351 and 7.52 ± 0.17 µM for ZINC000253403245. Thus, the screened compounds seem to have good potential as therapeutic candidates for leishmaniasis.
Screening of genes interacting with high myopia and neuropsychiatric disorders
Authors: Liu Yang , Liu Yang , Zhang Wen , Xue Zhong-Qi , Zhang Fang-Xia , Xu Wei-Gang , Zhuang Wen-Juan
Published: October 2023

Clinical studies have demonstrated an association between high myopia (HM) and neuropsychiatric disorders; however, the underlying mechanism of the association is not clear. We used whole exome sequencing (WES) in combination with the Genetic Variants Classification Criteria and Guidelines published by the American College of Medical Genetics (ACMG) and bioinformatics analysis to clarify the interrelationship between candidate genes. Causative genes for ocular diseases (45.38%) followed by neuropsychiatric disorders (22.69%) accounted for the highest proportion of genes that exhibited high pathogenicity in HM patients were found. Four pathogenic gene mutations were identified according to ACMG guidelines: c.164_165insACAGCA and c.C1760T in POLG, c.G1291A in COL5A1, and c.G10242T in ZNF469. Three causative genes for neuropsychiatric diseases, PTPRN2, PCDH15 and CDH23, were found to fall at the HM locus. The above results suggest that these genes may interact in high myopia and neuropsychiatric diseases.
No transfer of arousal from other’s eyes in Williams syndrome
Authors: Kleberg Johan Lundin , Hallman Astrid E. Z. , Galazka Martyna A. , Riby Deborah M. , Bölte Sven , Willfors Charlotte , Fawcett Christine , Nordgren Ann
Published: October 2023

Typically developing humans automatically synchronize their arousal levels, resulting in pupillary contagion, or spontaneous adaptation of pupil size to that of others. This phenomenon emerges in infancy and is believed to facilitate social interaction. Williams syndrome (WS) is a genetic condition characterized by a hyper-social personality and social interaction challenges. Pupillary contagion was examined in individuals with WS (n = 44), age-parallel-matched typically developing children and adults (n = 65), and infants (n = 79). Bayesian statistics were used. As a group, people with WS did not show pupillary contagion (Bayes factors supporting the null: 25–50) whereas control groups did. This suggests a very early emerging atypical developmental trajectory. In WS, higher pupillary contagion was associated with lower autistic symptoms of social communication. Diminished synchronization of arousal may explain why individuals with WS have social challenges, whereas synchronization of arousal is not a necessary correlate of high social motivation.
Effects of elevated temperatures on the mechanical properties of laterized concrete
Authors: Ukpata Joseph O. , Ewa Desmond E. , Liwhuliwhe Joseph U. , Alaneme George Uwadiegwu , Obeten Koyonor E.
Published: October 2023

This study explored the impact of elevated temperatures on the residual structural properties of concrete made with a non-conventional fine aggregate such as laterite and quarry dust. In regions prone to high temperatures, such as tropical climates, the structural integrity of concrete can be compromised when exposed to elevated temperatures. Concrete samples were subjected to high temperatures (250 °C) and compared with control samples tested under normal conditions. In this research, the concrete mix was altered by replacing fine aggregates with different combinations of laterite (Lat) and quarry dust (QD) at varying percentages: 10%Lat:90%QD, 25%Lat:75%QD, 90%Lat:10%QD, 75%Lat:25%QD, and 50%Lat:50%QD. The physical properties of the constituent aggregates, including sand, laterite, quarry dust, and granite, were assessed, and an experimental mix was designed. The concrete samples underwent curing for 3, 7, 14, and 28 days, and their mechanical properties, specifically compression and flexural strength, were analyzed. The results demonstrated that as the percentage of laterite in the concrete matrix increased, there was a linear improvement in performance in terms of density, sorptivity, and strength gain. The maximum compressive strength reached 32.80 N/mm2 at 90% laterite replacement. However, flexural strength showed a different response, with the highest strength of 5.99 N/mm2 observed at 50% laterite replacement, after which strength declined with further increases in the laterite ratio. For economic and engineering considerations, it is recommended to use 25% laterite replacement with sand to produce grade 30 concrete, while 50% laterite replacement is suitable for grade-25 concrete. Importantly, the study found that a temperature of 250 °C did not significantly affect concrete strength, with changes of no more than 5%, which is consistent with expectations for conventional concrete. Furthermore, this research suggests that an optimal laterite replacement range of 25–50% should be considered when using laterite in concrete production.
Serum exosomal microRNA-1258 may as a novel biomarker for the diagnosis of acute exacerbations of chronic obstructive pulmonary disease
Authors: Wang Fei , Yang Boxin , Qiao Jiao , Bai Linlu , Li Zijing , Sun Wenyuan , Liu Qi , Yang Shuo , Cui Liyan
Published: October 2023

Acute exacerbation chronic obstructive pulmonary disease (AECOPD) has a high mortality rate. However, there is no efficiency biomarker for diagnosing AECOPD. The purpose of this study was to find biomarkers that can quickly and accurately diagnose AECOPD.45 normal controls (NC), 42 patients with stable COPD (SCOPD), and 66 patients with AECOPD were enrolled in our study. Serum exosomes were isolated by ultracentrifuge and verified by morphology and specific biomarkers. Fluorescent quantitation polymerase chain reaction (qRT-PCR) was used to detect the expression of micro RNAs (miRNAs), including miR-660-5p, miR-1258, miR-182-3p, miR-148a-3p, miR-27a-5p and miR-497-5p in serum exosomes and serum. Logistic regression and machine learning methods were used to constructed the diagnostic models of AECOPD. The levels of miR-1258 in the patients with AECOPD were higher than other groups (p < 0.001). The ability of exosomal miR-1258 (AUC = 0.851) to identify AECOPD from SCOPD was superior to other biomarkers, and the combination of exosomal miR-1258 and NLR can increase the AUC to 0.944, with a sensitivity of 81.82%, and specificity of 97.62%. The cross-validation of the models displayed that the logistic regression model based on exosomal miR-1258, NLR and neutrophil count had the best accuracy (0.880) in diagnosing AECOPD from SCOPD. The three most correlated biomarkers with serum exosome miR-1258 were neutrophil count (r = 0.57, p < 0.001), WBC (r = 0.50, p < 0.001) and serum miR-1258 (r = 0.33, p < 0.001). In conclusion, serum exosomal miR-1258 is associated with inflammation, and can be used as a valuable and reliable biomarker for the diagnosis of AECOPD, and the establishment of diagnostic model based on miR-1258, NLR and neutrophils count can help to improving the accuracy of AECOPD diagnosis.
I-gel Plus acts as a superior conduit for fiberoptic intubation than standard i-gel
Authors: Chaki Tomohiro , Tachibana Shunsuke , Kumita Sho , Sato Satoshi , Hirahata Tomoki , Ikeshima Yuta , Ohsaki Yuki , Yamakage Michiaki
Published: October 2023

The supraglottic airway (SGA) is widely used. I-gel Plus is a next-generation i-gel with some improvements, including facilitation of fiberoptic tracheal intubation (FOI). To compare the performance of i-gel Plus and standard i-gel as conduits for FOI, a Thiel-embalmed cadaveric study was conducted. Twenty-two anesthesiologists were enrolled as operators in Experiment 1. The i-gel Plus and standard i-gel were inserted into one cadaver, and the FOI was performed through each SGA. The primary outcome was time required for FOI. The secondary outcomes were the number of attempts and visual analog scale (VAS) score for difficulty in FOI. Moreover, fiberoptic views of the vocal cords in each SGA were assessed by an attending anesthesiologist using nine cadavers in Experiment 2. The percentage of glottic opening (POGO) score without fiberscope tip upward flexion and upward angle of the fiberscope tip to obtain a 100% POGO score were evaluated as secondary outcomes. The time for FOI through i-gel Plus was significantly shorter than that through standard i-gel (median (IQR), i-gel Plus: 30.3 (25.4–39.0) s, vs standard i-gel: 54.7 (29.6–135.0) s; median of differences, 24.4 s; adjusted 95% confidence interval, 3.0–105.7; adjusted P = 0.040). Although the number of attempts for successful FOI was not significantly different, the VAS score for difficulty in the i-gel Plus group was significantly lower (easier) than that in the standard i-gel group. Moreover, i-gel Plus required a significantly smaller upward angle of the fiberscope tip to obtain a 100% POGO score. FOI can be performed more easily using i-gel Plus than using standard i-gel because of the improved fiberoptic visibility of vocal cords.