Recent Submissions

  • Synthesis, biological evaluation, and SAR studies of 14β-phenylacetyl substituted 17-cyclopropylmethyl-7, 8-dihydronoroxymorphinones derivatives: ligands with mixed NOP and opioid receptor profile

    Kumar, Vinod; Polgar, Willma E.; Cami-Kobeci, Gerta; Thomas, Mark P.; Khroyan, Taline V.; Toll, Lawrence; Husbands, Stephen M.; ; Central University of Punjab; SRI International; et al. (Frontiers, 2018-09-19)
    A series of 14β-acyl substituted 17-cyclopropylmethyl-7,8-dihydronoroxymorphinone compounds has been synthesized and evaluated for affinity and efficacy for mu (MOP), kappa (KOP), and delta (DOP) opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors. The majority of the new ligands displayed high binding affinities for the three opioid receptors, and moderate affinity for NOP receptors. The affinities for NOP receptors are of particular interest as most classical opioid ligands do not bind to NOP receptors. The predominant activity in the [35S]GTPγS assay was partial agonism at each receptor. The results are consistent with our prediction that an appropriate 14β side chain would access a binding site within the NOP receptor and result in substantially higher affinity than displayed by the parent compound naltrexone. Molecular modeling studies, utilizing the recently reported structure of the NOP receptor, are also consistent with this interpretation.
  • PPL-138 (BU10038): a bifunctional NOP/mu partial agonist that reduces cocaine self-administration in rats

    Cippitelli, Andrea; Martinez, Madeline; Zribi, Gilles; Cami-Kobeci, Gerta; Husbands, Stephen M.; Toll, Lawrence; ; Florida Atlantic University; University of Bedfordshire; University of Bath (Elsevier, 2022-06-15)
    The search for new and effective treatments for cocaine use disorder (CUD) is a priority. We determined whether PPL-138 (BU10038), a compound with partial agonist activity at both nociceptin opioid peptide (NOP) and mu-opioid receptors, reduces cocaine consumption, reinstatement, and whether the compound itself produces reinforcing effects in rats. Using an intermittent access (IntA) cocaine self-administration procedure, we found that PPL-138 (0.1 and 0.3 mg/kg) effectively decreased the total number of cocaine infusions and burst-like cocaine intake in both male and female rats. Responses for food in an IntA model of food self-administration were not altered for either sex, although locomotor activity was increased in female but not male rats. Blockade of NOP receptors with the selective antagonist J-113397 (5 mg/kg) did not prevent the PPL-138-induced suppression of cocaine self-administration, whereas blockade of mu-opioid receptors by naltrexone (1 mg/kg) reversed such effect. Consistently, treatment with morphine (1, 3, and 10 mg/kg) dose-dependently reduced IntA cocaine self-administration measures. PPL-138 also reduced reinstatement of cocaine seeking at all doses examined. Although an initial treatment with PPL-138 (2.5, 10, and 40 μg/kg/infusion) appeared rewarding, the compound did not maintain self-administration behavior. Animals treated with PPL-138 showed initial suppression of cocaine self-administration, which was eliminated following repeated daily dosing. However, suppression of cocaine self-administration was retained when subsequent PPL-138 treatments were administered 48 h apart. These findings demonstrate that the approach of combining partial NOP/mu-opioid activation successfully reduces cocaine use, but properties of PPL-138 seem to depend on the timing of drug administration.
  • OREX-1038: a potential new treatment for pain with low abuse liability and limited adverse effects

    Gerak, Lisa R.; Maguire, David R.; Cami-Kobeci, Gerta; Olson, Keith M.; Traynor, John R.; Husbands, Stephen M.; France, Charles P.; Acevedo, Lisette; Belli, Barbara; Flynn, Peter; et al. (Lippincott, Williams & Wilkins, 2022-09-30)
    Drugs targeting mu opioid receptors are the mainstay of clinical practice for treating moderate-to-severe pain. While they can offer excellent analgesia, their use can be limited by adverse effects, including constipation, respiratory depression, tolerance, and abuse liability. Multifunctional ligands acting at mu opioid and nociceptin/orphanin FQ peptide receptors might provide antinociception with substantially improved adverse-effect profiles. This study explored one of these ligands, OREX-1038 (BU10038), in several assays in rodents and nonhuman primates. Binding and functional studies confirmed OREX-1038 to be a low-efficacy agonist at mu opioid and nociceptin/orphanin FQ peptide receptors and an antagonist at delta and kappa opioid receptors with selectivity for opioid receptors over other proteins. OREX-1038 had long-acting antinociceptive effects in postsurgical and complete Freund's adjuvant (CFA)-induced thermal hyperalgesia assays in rats and a warm water tail-withdrawal assay in monkeys. OREX-1038 was active for at least 24 h in each antinociception assay, and its effects in monkeys did not diminish over 22 days of daily administration. This activity was coupled with limited effects on physiological signs (arterial pressure, heart rate, and body temperature) and no evidence of withdrawal after administration of naltrexone or discontinuation of treatment in monkeys receiving OREX-1038 daily. Over a range of doses, OREX-1038 was only transiently self-administered, which diminished rapidly to nonsignificant levels; overall, both OREX-1038 and buprenorphine maintained less responding than remifentanil. These results support the concept of dual mu and nociceptin/orphanin FQ peptide receptor partial agonists having improved pharmacological profiles compared with opioids currently used to treat pain.
  • An important role for RPRD1B in the heat shock response

    Cugusi, Simona; Bajpe, Prashanth Kumar; Mitter, Richard; Patel, Harshil; Stewart, Aengus; Svejstrup, Jesper Q.; ; Francis Crick Institute; University of Copenhagen (Taylor and Francis, 2022-10-22)
    During the heat shock response (HSR), heat shock factor (HSF1 in mammals) binds to target gene promoters, resulting in increased expression of heat shock proteins that help maintain protein homeostasis and ensure cell survival. Besides HSF1, only a relatively few transcription factors with a specific role in ensuring correctly regulated gene expression during the HSR have been described. Here, we use proteomic and genomic (CRISPR) screening to identify a role for RPRD1B in the response to heat shock. Indeed, cells depleted for RPRD1B are heat shock sensitive and show decreased expression of key heat shock proteins (HSPs). These results add to our understanding of the connection between basic gene expression mechanisms and the HSR.
  • Translation stress and collided ribosomes are co-activators of cGAS

    Wan, Li; Juszkiewicz, Szymon; Blears, Daniel; Bajpe, Prashanth Kumar; Han, Zhong; Faull, Peter; Mitter, Richard; Stewart, Aengus; Snijders, Ambrosius P.; Hegde, Ramanujan S.; et al. (Cell Press, 2021-07-01)
    The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway senses cytosolic DNA and induces interferon-stimulated genes (ISGs) to activate the innate immune system. Here, we report the unexpected discovery that cGAS also senses dysfunctional protein production. Purified ribosomes interact directly with cGAS and stimulate its DNA-dependent activity in vitro. Disruption of the ribosome-associated protein quality control (RQC) pathway, which detects and resolves ribosome collision during translation, results in cGAS-dependent ISG expression and causes re-localization of cGAS from the nucleus to the cytosol. Indeed, cGAS preferentially binds collided ribosomes in vitro, and orthogonal perturbations that result in elevated levels of collided ribosomes and RQC activation cause sub-cellular re-localization of cGAS and ribosome binding in vivo as well. Thus, translation stress potently increases DNA-dependent cGAS activation. These findings have implications for the inflammatory response to viral infection and tumorigenesis, both of which substantially reprogram cellular protein synthesis.
  • Mutation of daf-2 extends lifespan via tissue-specific effectors that suppress distinct life-limiting pathologies

    Zhao, Yuan; Zhang, Bruce; Marcu, Ioan; Athar, Faria; Wang, Hongyua; Galimov, Evgeniy R; Chapman, Hannah; Gems, David; ; University College London (Anatomical Society and John Wiley & Sons Ltd., 2021-02-20)
    In aging Caenorhabditis elegans, as in higher organisms, there is more than one cause of death. C. elegans exhibit early death with a swollen, infected pharynx (P death), and later death with pharyngeal atrophy (p death). Interventions that alter lifespan can differentially affect frequency and timing of each type of death, generating complex survival curve shapes. Here, we use mortality deconvolution analysis to investigate how reduction of insulin/IGF-1 signaling (IIS), which increases lifespan (the Age phenotype), affects different forms of death. All daf-2 insulin/IGF-1 receptor mutants exhibit increased lifespan in the p subpopulation (p Age), while pleiotropic class 2 daf-2 mutants show an additional marked reduction in P death frequency. The latter is promoted by pharyngeal expression of the IIS-regulated DAF-16 FOXO transcription factor, and at higher temperature by reduced pharyngeal pumping rate. Pharyngeal DAF-16 also promotes p Age in class 2 daf-2 mutants, revealing a previously unknown role for the pharynx in the regulation of aging. Necropsy analysis of daf-2 interactions with the daf-12 steroid receptor implies that previously described opposing effects of daf-12 on daf-2 longevity are attributable to internal hatching of larvae, rather than complex interactions between insulin/IGF-1 and steroid signaling. These findings support the view that wild-type IIS acts through multiple distinct mechanisms which promote different life-limiting pathologies, each of which contribute to late-life mortality. This study further demonstrates the utility of mortality deconvolution analysis to better understand the genetics of lifespan.
  • Influence of environmental factors and genome diversity on cumulative COVID-19 cases in the highland region of China: comparative correlational study

    Deji, Zhuoga; Tong, Yuantao; Huang, Honglian; Zhang, Zeyu; Fang, Meng; Crabbe, M. James C.; Zhang, Xiaoyan; Wang, Ying; University of Bedfordshire; Tongji University; et al. (JMIR Publications, 2024-03-25)
    Background: The novel coronavirus SARS-CoV-2 caused the global COVID-19 pandemic. Emerging reports support lower mortality and reduced case numbers in highland areas; however, comparative studies on the cumulative impact of environmental factors and viral genetic diversity on COVID-19 infection rates have not been performed to date. Objective: The aims of this study were to determine the difference in COVID-19 infection rates between high and low altitudes, and to explore whether the difference in the pandemic trend in the high-altitude region of China compared to that of the lowlands is influenced by environmental factors, population density, and biological mechanisms. Methods: We examined the correlation between population density and COVID-19 cases through linear regression. A zero-shot model was applied to identify possible factors correlated to COVID-19 infection. We further analyzed the correlation of meteorological and air quality factors with infection cases using the Spearman correlation coefficient. Mixed-effects multiple linear regression was applied to evaluate the associations between selected factors and COVID-19 cases adjusting for covariates. Lastly, the relationship between environmental factors and mutation frequency was evaluated using the same correlation techniques mentioned above. Results: Among the 24,826 confirmed COVID-19 cases reported from 40 cities in China from January 23, 2020, to July 7, 2022, 98.4% (n=24,430) were found in the lowlands. Population density was positively correlated with COVID-19 cases in all regions (ρ=0.641, P=.003). In high-altitude areas, the number of COVID-19 cases was negatively associated with temperature, sunlight hours, and UV index (P=.003, P=.001, and P=.009, respectively) and was positively associated with wind speed (ρ=0.388, P<.001), whereas no correlation was found between meteorological factors and COVID-19 cases in the lowlands. After controlling for covariates, the mixed-effects model also showed positive associations of fine particulate matter (PM2.5) and carbon monoxide (CO) with COVID-19 cases (P=.002 and P<.001, respectively). Sequence variant analysis showed lower genetic diversity among nucleotides for each SARS-CoV-2 genome (P<.001) and three open reading frames (P<.001) in high altitudes compared to 300 sequences analyzed from low altitudes. Moreover, the frequencies of 44 nonsynonymous mutations and 32 synonymous mutations were significantly different between the high- and low-altitude groups (P<.001, mutation frequency>0.1). Key nonsynonymous mutations showed positive correlations with altitude, wind speed, and air pressure and showed negative correlations with temperature, UV index, and sunlight hours. Conclusions: By comparison with the lowlands, the number of confirmed COVID-19 cases was substantially lower in high-altitude regions of China, and the population density, temperature, sunlight hours, UV index, wind speed, PM2.5, and CO influenced the cumulative pandemic trend in the highlands. The identified influence of environmental factors on SARS-CoV-2 sequence variants adds knowledge of the impact of altitude on COVID-19 infection, offering novel suggestions for preventive intervention.
  • Preparation of a novel metallothionein-AuNP composite material by genetic modification and Au–S covalent combination

    Li, Xuefen; Liu, Hui; Wang, Yuxia; Crabbe, M. James C.; Wang, Lan; Ma, Wenli; Ren, Zhumei; Shanxi University; University of Oxford; University of Bedfordshire (Elsevier, 2024-02-05)
    Metallothionein (MTs) can be used in the prevention and treatment of tumors and diabetes due to its antioxidant properties. However, it is necessary to solve its non-transmembrane properties and further improve its antioxidant activity, increase its fluorescence visualization and enhance its stability to meet practical applications in the biomedical field. Here, we report the preparation of a novel metallothionein-AuNP composite material with high transmembrane ability, fluorescence visualization, antioxidant activity, and stability by genetic modification (introducing transduction peptide TAT, fluorescence tag GFP and increasing sulfydryl groups) and immobilization technology (covalently bonding with AuNPs). The transmembrane activity of modified proteins was verified by immunofluorescence. Increasing the sulfhydryl content within a certain range can enhance the antioxidant activity of the protein. In addition, GFP were used to further simplify the imaging of the metallothionein-AuNP composite in cells. XPS results indicated that AuNPs can immobilize metallothionein through Au–S covalent bonds. TGA characterization and degradation experiments showed that thermal and degradation stability of the immobilized material was significantly improved. This work provides new ideas to construct metallothionein composites with high transmembrane ability, antioxidant activity, fluorescence visualization and stability to meet novel applications in the biomedical field.
  • Cancer development in hepatocytes by long-term induction of hypoxic hepatocellular carcinoma cell (HCC)-derived exosomes in vivo and in vitro

    Ju, Tuoyu; Dong, Jianjun; Wang, Bowei; Qu, Kaige; Cheng, Can; He, Xiuxia; Tian, Yanling; Crabbe, M. James C.; Wang, Zuobin; Chen, Yujuan (ACS, 2023-10-16)
    Hypoxic tumor cell-derived exosomes play a key role in the occurrence, development, and metastasis of tumors. However, the mechanism of hypoxia-mediated metastasis remains unclear. In this study, hypoxic hepatocellular carcinoma cell (HCC-LM3)-derived exosomes (H-LM3-exos) were used to induce hepatocytes (HL-7702) over a long term (40 passages in 120 days). A nude mouse experiment further verified the effect of H-LM3-exos on tumor growth and metastasis. The process of cancer development in hepatocytes induced by H-LM3-exos was analyzed using both biological and physical techniques, and the results showed that the proliferation and soft agar growth abilities of the transformed cells were enhanced. The concentration of tumor markers secreted by transformed cells was increased, the cytoskeleton was disordered, and the migration ability was enhanced and was accompanied by epithelial−mesenchymal transition (EMT). Transcriptome results showed that differentially expressed genes between transformed cells and hepatocytes were enriched in cancer-related signaling pathways. The degree of cancer development in transformed cells was enhanced by an increase in H-LM3-exos-induced passages. Nude mice treated with different concentrations of H-LM3-exos showed different degrees of tumor growth and liver lesions. The physical properties of the cells were characterized by atomic force microscopy. Compared with the hepatocytes, the height and roughness of the transformed cells were increased, while the adhesion and elastic modulus were decreased. The changes in physical properties of primary tumor cells and hepatocytes in nude mice were consistent with this trend. Our study linking omics with the physical properties of cells provides a new direction for studying the mechanisms of cancer development and metastasis.
  • Impacts of marine cloud brightening scheme on climatic extremes in the Tibetan Plateau

    Zhang, Zhihua; Zhu, Yuanzhuo; Crabbe, M. James C. (De Gruyter, 2023-09-29)
    As an ecologically fragile plateau and major water source in Asia, the Tibetan Plateau (TP) has grown warmer over recent decades, contributing to frequent occurrence of extreme climate events. It is urgently needed to find a suitable option to mitigate climate change impacts in the TP. The marine cloud brightening (MCB) scheme is proposed to mitigate global warming through the increasing cloud droplet number concentration of low marine clouds to reflect some solar radiation back into space. Until now, impacts of MCB scheme on the TP have not been investigated. In this study, we utilized 13 Expert Team on Climate Change Detection and Indices to assess the evolution of climate extremes over the TP with/without MCB implementation. We found that although the MCB is implemented over ocean only, it would cause significant changes on climate extremes in the TP which is very far from oceans and much higher than sea level. During 2030–2059, MCB implementation can decrease warm temperature extremes, leading to a significant decrease in the TXx index by 6–18°C, the TX90p index by 15–45 days, and the TN90p index by 15–50 days. MCB implementation would also have some cooling effects on cold temperature extremes, leading to an increase in the ID index by 30–80 days, the TX10p index by 22–32 days, and the TN10p index by about 12 days and a decrease in the TNn index by 0.5–1.5°C. Although MCB implementation would not have much impacts on precipitation extremes, it would significantly increase the area of the region with <10% drought frequency, and increase the drought intensity in the west of Lhasa city.
  • Effect of vegetation blanket cover with different materials on soil microbial community structure of opencast coal mines in arid areas

    Wang, Ziyin; Liu, Huili; Crabbe, M. James C.; Zhao, Xiaoyu; Liu, Bingru; North Minzu University; Oxford University; University of Bedfordshire; Shanxi University (John Wiley and Sons Ltd, 2023-09-04)
    Vegetation blanket restoration of mine soils provides a diverse environment for soil microbes, but the effects of vegetation blanket cover on soil physicochemical properties, microbial structure, and diversity are not well understood, particularly in arid areas. In this study, high-throughput sequencing was used to examine the microbial community at Dafeng Mine, the Helan Mountains, Ningxia, China. Soil microbial communities were analyzed with four different materials: 100% straw, 50% straw–50% coconut, and 100% coconut vegetation blanket types, and a bare ground control (CK). The results showed that the contents of soil total nitrogen (TN), available potassium (AP), urease, and catalase were significantly increased in different types of vegetation blankets. High-throughput sequencing showed that the straw vegetation blanket increased bacterial diversity, while the coconut vegetation blanket increased fungal diversity. The main influencing factors of the dominant bacterial phylum were total nitrogen, catalase, urease, protease, soil water content (WC), soil organic carbon (SOC), and electrical conductivity (EC). The main influencing factor of the dominant fungal phylum was soil water content. These results show that compared with straw vegetation blankets, coconut, and straw–coconut vegetation blanket mulches are more likely to improve soil physicochemical properties, increase the diversity and abundance of soil microorganisms and improve the structural composition of the community, thus improving the soil environment in dryland mining areas. However, further research is needed as to which is the more significant environmental improvement, coconut or straw–coconut vegetation blankets.
  • Integrative analysis of the metabolome and transcriptome reveals the potential mechanism of fruit flavor formation in wild hawthorn Crataegus chungtienensis

    Wu, Xien; Luo, Dengli; Zhang, Yingmin; Jin, Ling; Crabbe, M. James C.; Qiao, Qin; Li, Guodong; Zhang, Ti-Cao; ; Yunnan University of Chinese Medicine; et al. (Elsevier, 2023-02-24)
    Hawthorns are important medicinal and edible plants with a long history of health protection in China. Besides cultivated hawthorn, other wild hawthorns may also have excellent medicinal and edible value, such as Crataeguschungtienensis, an endemic species distributed in the Southwest of China. In this study, by integrating the flavor-related metabolome and transcriptome data of the ripening fruit of C. chungtienensis, we have developed an understanding of the formation of hawthorn fruit quality. The results show that a total of 849 metabolites were detected in the young and mature fruit of C. chungtienensis, of which flavonoids were the most detected metabolites. Among the differentially accumulated metabolites, stachyose, maltotetraose and cis-aconitic acid were significantly increased during fruit ripening, and these may be important metabolites affecting fruit flavor change. Moreover, several flavonoids and terpenoids were reduced after fruit ripening compared with young fruit. Therefore, using the unripe fruit of C. chungtienensis may allow us to obtain more medicinal active ingredients such as flavonoids and terpenoids. Furthermore, we screened out some differentially expressed genes (DEGs) related to fruit quality formation, which had important relationships with differentially accumulated sugars, acids, flavonoids and terpenoids. Our study provides new insights into flavor formation in wild hawthorn during fruit development and ripening, and at the same time this study lays the foundation for the improvement of hawthorn fruit flavor.
  • The effect of high altitude on ephedrine content and metabolic variations in two species of Ephedra

    Lu, Mengnan; He, Wenjia; Xu, Ziyan; Lu, Yan; Crabbe, M. James C.; De, Ji; ; Tibet University; Tibet Academy of Agricultural and Animal Husbandry Sciences; Fudan University; et al. (Frontiers, 2023-10-16)
    Ephedra is an important plant in Chinese medicine; however, there are few reports on two species of Ephedra which are distributed at high altitudes from 3000 to 5200 meters. We collected a total of 84 individuals representing five Ephedra gerardiana and nine Ephedra saxatilis populations respectively located from 3158 to 5200 meters altitude, and determined the relative content of 213 metabolites using UHPLC-MS/MS (Ultra-High-Performance Liquid Chromatography-tandem mass spectrometry). 37 Chemical compositions were annotated using the KEGG (Kyoto Encyclopaedia of Genes and Genomes) database. From the top five significant enrichments in metabolic KEGG pathway analysis, we found a total of 166 compounds belonging to phenylpropanoids, 123 flavonoids, 67 metabolites carried by ABC transporters, and 61 in purine metabolism. We identified the top 8 altitude-related compounds in two species. Ephedrine and pseudoephedrine were found to be associated with altitude in both E. saxatilis and E. gerardiana. To verify which environmental factors influenced the metabolic content, the soil moisture and temperature of each population site were collected, and quantitative analysis of ephedrine and pseudoephedrine was performed using UHPLC-MS (Ultra-High-Performance liquid chromatography-tandem mass spectrometry). After detection, soil moisture ranged from 0.074 to 0.177 mm3/mm3, and temperature ranged from 9.7°C to 23.9°C. The content of ephedrine ranged from (0.84 ± 0.49)% to (2.01 ± 0.41)% in E. saxatilis, which was positively correlated with soil moisture; the content of pseudoephedrine ranged from (0.72 ± 0.45)% to (1.11 ± 0.57)% and was negatively correlated with soil moisture. In contrast to these results, in E. gerardiana, the content of ephedrine and pseudoephedrine was negatively correlated with soil moisture. Furthermore, the trends of alkaloid contents in two kinds of Ephedra were similar when the temperature was lower than 17°C even if the sum was various. With the increase in soil moisture and temperature, the total alkaloid content of E. saxatilis was higher than that of E. gerardiana. When the soil moisture was lower, the alkaloid content of the two Ephedra species was higher. These results provide useful data for the future separation of new compounds, and for seed homogeneous growth to determine artificial breeding of Ephedra located at high altitudes.
  • Use of atomic force microscopy in UVB-induced chromosome damage provides important bioinformation for cell damage assessment

    Wang, Bowei; Dong, Jianjun; Yang, Fan; Ju, Tuoyu; Li, Jiani; Crabbe, M. James C.; Wang, Ying; Tian, Yanling; Wang, Zuobin (ACS, 2023-09-08)
    The chromosomal structure derived from UVB-stimulated HaCaT cells was detected by atomic force microscopy (AFM) to evaluate the effect of UVB irradiation. The results showed that the higher the UVB irradiation dose, the more the cells that had chromosome aberration. At the same time, different representative types of chromosome structural aberrations were investigated. We also revealed damage to both DNA and cells under the corresponding irradiation doses. It was found that the degree of DNA damage was directly proportional to the irradiation dose. The mechanical properties of cells were also changed after UVB irradiation, suggesting that cells experienced a series of chain reactions from inside to outside after irradiation. The highresolution imaging of chromosome structures by AFM after UVB irradiation enables us to relate the damage between chromosomes, DNA, and cells caused by UVB irradiation and provides specific information on genetic effects.
  • Large-scale biomedical relation extraction across diverse relation types: model development and usability study on COVID-19

    Zhang, Zeyu; Fang, Meng; Wu, Rebecca; Zong, Hui; Huang, Honglian; Tong, Yuantao; Xie, Yujia; Cheng, Shiyang; Wei, Ziyi; Crabbe, M. James C.; et al. (JMIR Publications, 2023-09-20)
    Biomedical relation extraction (RE) is of great importance for researchers to conduct systematic biomedical studies. It not only helps knowledge mining, such as knowledge graphs and novel knowledge discovery, but also promotes translational applications, such as clinical diagnosis, decision-making, and precision medicine. However, the relations between biomedical entities are complex and diverse, and comprehensive biomedical RE is not yet well established. We aimed to investigate and improve large-scale RE with diverse relation types and conduct usability studies with application scenarios to optimize biomedical text mining. Data sets containing 125 relation types with different entity semantic levels were constructed to evaluate the impact of entity semantic information on RE, and performance analysis was conducted on different model architectures and domain models. This study also proposed a continued pretraining strategy and integrated models with scripts into a tool. Furthermore, this study applied RE to the COVID-19 corpus with article topics and application scenarios of clinical interest to assess and demonstrate its biological interpretability and usability. The performance analysis revealed that RE achieves the best performance when the detailed semantic type is provided. For a single model, PubMedBERT with continued pretraining performed the best, with an F1-score of 0.8998. Usability studies on COVID-19 demonstrated the interpretability and usability of RE, and a relation graph database was constructed, which was used to reveal existing and novel drug paths with edge explanations. The models (including pretrained and fine-tuned models), integrated tool (Docker), and generated data (including the COVID-19 relation graph database and drug paths) have been made publicly available to the biomedical text mining community and clinical researchers. This study provided a comprehensive analysis of RE with diverse relation types. Optimized RE models and tools for diverse relation types were developed, which can be widely used in biomedical text mining. Our usability studies provided a proof-of-concept demonstration of how large-scale RE can be leveraged to facilitate novel research.
  • Multifractal features and dynamical thresholds of temperature extremes in Bangladesh

    Liu, Anxin; Zhang, Zhihua; Crabbe, M. James C.; Das, Lipon Chandra; Shandong University; Beijing Normal University; Oxford Universi; University of Bedfordshire; University of Chittagong (MDPI, 2023-07-13)
    Multifractal detrended fluctuation analysis (DFA) can extract multi-scaling behavior and measure long-range correlations in climatic time series. In this study, with the help of multifractal DFA, we investigated the scaling behavior of daily minimum/maximum temperatures during the years 1989–2019 from 34 meteorological stations in Bangladesh. We revealed spatial patterns, topographic impacts and global warming impacts of long-range correlations embedded in small and large fluctuations in temperature time series. Meanwhile, we developed a multifractal DFA-based algorithm to dynamically determine thresholds to discriminate extreme and non-extreme events in climate systems and applied it to analyze the frequency and trends of temperature extremes in Bangladesh. Compared with widely-used percentile thresholds, the extreme climate events captured in our algorithm are more reliable since they are determined dynamically by the climate system itself.
  • Do research incentives promote researchers’ mental health?

    Gu, Liujian; Wang, Tao; Wang, Chuanyi; Crabbe, M. James C.; Yue, Xiao-Guang; Tsinghua University; Oxford University; University of Bedfordshire (Tech Science Press, 2023-07-10)
    Researchers have a higher risk of anxiety and depression than the general population, so it is important to promote researchers’ mental health. Method: Based on the data from 3210 global researchers surveyed by the journal Nature in 2021, confirmatory factor analysis, OLS regression and other regressions were used to explore the research incentive dimensions and their effects on researchers’ mental health. Results: (1) Material incentive factors, work-family life balance factors, good organizational environment and spiritual motivation had significant positive effects on researchers’ mental health. (2) The spiritual motivation could better promote researchers’ mental health than the other factors. (3) Heterogeneity analysis showed that material incentive factors and spiritual motivation created more significant stimulating effects on the mental health of humanities and social sciences researchers. Work-family life balance factors were more effective in promoting the mental health of the mid-career group and the overtime group. Conclusion: Application of the four research incentives resulted in lower likelihood of anxiety or depression among researchers, and special attention should be paid to the role of the spiritual motivation. In order to promote researchers’ mental health, different incentives should be applied to different researcher groups to better improve researchers’ mental health.
  • Interaction between gut microbiota metabolites and dietary components in lipid metabolism and metabolic diseases

    Basnet, Til Bahadur; GC, Srijana; Basnet, Rajesh; Fatima, Sadia; Safdar, Mahpara; Sehar, Bismillah; Alsubaie, Ali Saad R.; Zeb, Falak; ; Fujian Medical University; et al. (Microbiology Society, 2023-06-23)
    Gut microbiota composition has caused perplexity in developing precision therapy to cure metabolic disorders. However, recent research has focused on using daily diet and natural bioactive compounds to correct gut microbiota dysbiosis and regulate host metabolism. Complex interactions between the gut microbiota and dietary compounds disrupt or integrate the gut barrier and lipid metabolism. In this review, we investigate the role of diet and bioactive natural compounds in gut microbiota dysbiosis and also the modulation of lipid metabolism by their metabolites. Recent studies have revealed that diet, natural compounds and phytochemicals impact significantly on lipid metabolism in animals and humans. These findings suggest that dietary components or natural bioactive compounds have a significant impact on microbial dysbiosis linked to metabolic diseases. The interaction between dietary components or natural bioactive compounds and gut microbiota metabolites can regulate lipid metabolism. Additionally, natural products can shape the gut microbiota and improve barrier integrity by interacting with gut metabolites and their precursors, even in unfavourable conditions, potentially contributing to the alignment of host physiology.
  • RNA-binding proteins and their emerging roles in cancer: beyond the tip of the iceberg

    Murphy, John J.; Surendranath, Kalpana; Kanagaraj, Radhakrishnan; University of Westminster; University of Bedfordshire; Sathyabama Institute of Science and Technology (MDPI, 2023-06-01)
    RNA-binding proteins (RBPs) represent a large family of proteins with an extensive array of roles that contribute to coordinating and directing multiple functions in RNA metabolism and transcription [...].
  • Thyroid-disrupting effects of exposure to fipronil and its metabolites from drinking water based on human thyroid follicular epithelial Nthy-ori 3‑1 cell lines

    Zhuang, Jianhui; Jiang, Zhiqiang; Chen, Dawei; Li, Jingguang; Crabbe, M. James C.; Qiu, Meiyue; Zheng, Yuxin; Qu, Weidong; Fudan University; China National Center for Food Safety Risk Assessment; et al. (ACS, 2023-04-06)
    Fipronil is a broad-spectrum insecticide used for plants and poultry. Owing to its widespread use, fipronil and its metabolites (fipronil sulfone, fipronil desulfinyl, and fipronil sulfide), termed FPM, can be frequently detected in drinking water and food. Fipronil can affect the thyroid function of animals, but the effects of FPM on the human thyroid remain unclear. We employed human thyroid follicular epithelial Nthy-ori 3-1 cells to examine combined cytotoxic responses, thyroid-related functional proteins including the sodium-iodide symporter (NIS), thyroid peroxidase (TPO), deiodinases I−III (DIO I−III), and the nuclear factor erythroid-derived factor 2−related factor 2 (NRF2) pathway induced by FPM of 1−1000-fold concentrations detected in school drinking water collected from a heavily contaminated area of the Huai River Basin. Thyroid-disrupting effects of FPM were evaluated by examining biomarkers of oxidative stress and thyroid function and tetraiodothyronine (T4) levels secreted by Nthy-ori 3-1 cells after FPM treatment. FPM activated the expression of NRF2, HO-1 (heme oxygenase 1), TPO, DIO I, and DIO II but inhibited NIS expression and increased the T4 level of thyrocytes, indicating that FPM can disrupt the function of human thyrocytes through oxidative pathways. Given the adverse impact of low FPM concentrations on human thyrocytes, supportive evidence from rodent studies, and the critical importance of thyroid hormones on development, the effects of FPM on the neurodevelopment and growth of children warrant priority attention.

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