Publications by authors named "Zhan Zhang"

330 Publications

Photoactivation of TGFβ/SMAD signaling pathway ameliorates adult hippocampal neurogenesis in Alzheimer's disease model.

Stem Cell Res Ther 2021 Jun 11;12(1):345. Epub 2021 Jun 11.

MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.

Background: Adult hippocampal neurogenesis (AHN) is restricted under the pathological conditions of neurodegenerative diseases, especially in Alzheimer's disease (AD). The drop of AHN reduces neural circuit plasticity, resulting in the decrease of the generation of newborn neurons in dentate gyrus (DG), which makes it difficult to recover from learning/memory dysfunction in AD, therefore, it is imperative to find a therapeutic strategy to promote neurogenesis and clarify its underlying mechanism involved.

Methods: Amyloid precursor protein/presenilin 1 (APP/PS1) mice were treated with photobiomodulation therapy (PBMT) for 0.1 mW/mm per day in the dark for 1 month (10 min for each day). The neural stem cells (NSCs) were isolated from hippocampus of APP/PS1 transgenic mice at E14, and the cells were treated with PBMT for 0.667 mW/mm in the dark (5 min for each time).

Results: In this study, photobiomodulation therapy (PBMT) is found to promote AHN in APP/PS1 mice. The latent transforming growth factor-β1 (LTGFβ1) was activated in vitro and in vivo during PBMT-induced AHN, which promoted the differentiation of hippocampal APP/PS1 NSCs into newborn neurons. In particular, behavioral experiments showed that PBMT enhanced the spatial learning/memory ability of APP/PS1 mice. Mechanistically, PBMT-stimulated reactive oxygen species (ROS) activates TGFβ/Smad signaling pathway to increase the interaction of the transcription factors Smad2/3 with Smad4 and competitively reduce the association of Smad1/5/9 with Smad4, thereby significantly upregulating the expression of doublecortin (Dcx)/neuronal class-III β-tubulin (Tuj1) and downregulating the expression of glial fibrillary acidic protein (GFAP). These in vitro effects were abrogated when eliminating ROS. Furthermore, specific inhibition of TGFβ receptor I (TGFβR I) attenuates the DNA-binding efficiency of Smad2/3 to the Dcx promotor triggered by PBMT.

Conclusion: Our study demonstrates that PBMT, as a viable therapeutic strategy, directs the adult hippocampal APP/PS1 NSCs differentiate towards neurons, which has great potential value for ameliorating the drop of AHN in Alzheimer's disease mice.
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http://dx.doi.org/10.1186/s13287-021-02399-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196501PMC
June 2021

In-depth analysis reveals complex molecular aetiology in a cohort of idiopathic cerebral palsy.

Brain 2021 Jun 2. Epub 2021 Jun 2.

Laboratory of Medical Systems Biology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, China.

Cerebral palsy is the most prevalent physical disability in children; however, its inherent molecular mechanisms remain unclear. In the present study, we performed in-depth clinical and molecular analysis on 120 idiopathic cerebral palsy families, and identified underlying detrimental genetic variants in 45% of these patients. In addition to germline variants, we found disease-related postzygotic mutations in approximately 6.7% of cerebral palsy patients. We found that patients with more severe motor impairments or a comorbidity of intellectual disability had a significantly higher chance of harboring disease-related variants. By a compilation of 114 known cerebral-palsy-related genes, we identified characteristic features in terms of inheritance and function, from which we proposed a dichotomous classification system according to the expression patterns of these genes and associated cognitive impairments. In two patients with both cerebral palsy and intellectual disability, we revealed that the defective TYW1, a tRNA hypermodification enzyme, caused primary microcephaly and problems in motion and cognition by hindering neuronal proliferation and migration. Furthermore, we developed an algorithm and demonstrated in mouse brains that this malfunctioning hypermodification specifically perturbed the translation of a subset of proteins involved in cell cycling. This finding provided a novel and interesting mechanism for congenital microcephaly. In another cerebral palsy patient with normal intelligence, we identified a mitochondrial enzyme GPAM, the hypomorphic form of which led to hypomyelination of the corticospinal tract in both human and mouse models. In addition, we confirmed that the aberrant Gpam in mice perturbed the lipid metabolism in astrocytes, resulting in suppressed astrocytic proliferation and a shortage of lipid contents supplied for oligodendrocytic myelination. Taken together, our findings elucidate novel aspects of the etiology of cerebral palsy and provide insights for future therapeutic strategies.
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http://dx.doi.org/10.1093/brain/awab209DOI Listing
June 2021

Gene body demethylation increases expression and is associated with self-pruning during grape genome duplication.

Hortic Res 2020 Jun 1;7(1):84. Epub 2020 Jun 1.

Beijing Key Laboratory of Grape Science and Enology and CAS Key Laboratory of Plant Resources, Institute of Botany, Chinese Academy of Sciences, Beijing, 100093, PR China.

A colchicine-induced autotetraploid grapevine exhibiting potentially valuable agronomic traits for grape production and breeding, including self-pruning, was identified. This study investigated DNA methylation variation and its role in gene expression during self-pruning in the autotetraploid grapevine. We used RNA-Seq to estimate differentially expressed genes between diploid and autotetraploid grapevine shoot tips. The genes showing increases in the autotetraploid were mainly related to stress response pathways, whereas those showing decreases in the autotetraploid were related to biological metabolism and biosynthesis. Whole-genome bisulfite sequencing was performed to produce single-base methylomes for the diploid and autotetraploid grapevines. Comparison between the methylomes revealed that they were conserved in CG and CHG contexts. In the autotetraploid grapevine, hypodifferentially methylated regions (DMRs) and hyper-DMRs in the gene body increased or decreased gene expression, respectively. Our results indicated that a hypo-DMR in the ACO1 gene body increased its expression and might promote self-pruning. This study reports that hypo-DMRs in the gene body increase gene expression in plants and reveals the mechanism underlying the changes in the modifications affecting gene expression during genome duplication. Overall, our results provide valuable information for understanding the relationships between DNA methylation, gene expression, and autotetraploid breeding in grape.
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http://dx.doi.org/10.1038/s41438-020-0303-7DOI Listing
June 2020

Effects of microplastics (MPs) and tributyltin (TBT) alone and in combination on bile acids and gut microbiota crosstalk in mice.

Ecotoxicol Environ Saf 2021 May 18;220:112345. Epub 2021 May 18.

Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, PR China; Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, PR China. Electronic address:

Microplastics (MPs) and tributyltin (TBT) are both potential environmental pollutants that enter organisms through the food chain and affect bodily functions. However, the effects and mechanisms of MPs and TBT exposure (especially the co-exposure of both pollutants) on mammals remain unclear. In this study, Ф5μm MPs (5MP) was administered alone or in combination with TBT to investigate the health risk of oral exposure in mice. All three treatments induced inflammation in the liver, altered gut microbiota composition and disturbed fecal bile acids profiles. In addition to decreasing triglyceride (TG) and increasing aspartate aminotransferase (AST) and macrophage-expressed gene 1 (Mpeg1), 5MP induced hepatic cholestasis by stimulating the expression of the cholesterol hydroxylase enzymes CYP8B1 and CYP27A1, and inhibiting multidrug resistance-associated protein 2 and 3 (MRP2, MRP3), and bile-salt export pump (BSEP) to prevent bile acids for entering the blood and bile. Correspondingly, 5MP treatment decreased 7-ketolithocholic acid (7-ketoLCA) and taurocholic acid (TCA), which were positively correlated with decreased Bacteroides and Marvinbryantia and negatively correlated with increased Bifidobacterium. In addition, TBT increased interferon γ (IFNγ) and Mpeg1 levels to induce inflammation, accompanied by decreased 7-ketoLCA, tauro-alpha-muricholic acid (T-alpha-MCA) and alpha-muricholic acid (alpha-MCA) levels, which were negatively related to Coriobacteriaceae_UCG-002 and Bifidobacterium. Co-exposure to 5MP and TBT also decreased TG and induced bile acids accumulation in the liver due to inhibited BSEP, which might be attributed to the co-regulation of decreased T-alpha-MCA and Harryflintia. In conclusion, the administration of 5MP and TBT alone and in combination could cause gut microbiome dysbiosis and subsequently alter bile acids profiles, while the combined exposure of 5MP and TBT weakened the toxic effects of 5MP and TBT alone.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112345DOI Listing
May 2021

Recent Advances in Metal-Phenolic Networks for Cancer Theranostics.

Small 2021 May 21:e2100314. Epub 2021 May 21.

Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, SAR, 999078, China.

Nanomedicine integrates different functional materials to realize the customization of carriers, aiming at increasing the cancer therapeutic efficacy and reducing the off-target toxicity. However, efforts on developing new drug carriers that combine precise diagnosis and accurate treatment have met challenges of uneasy synthesis, poor stability, difficult metabolism, and high cytotoxicity. Metal-phenolic networks (MPNs), making use of the coordination between phenolic ligands and metal ions, have emerged as promising candidates for nanomedicine, most notably through the service as multifunctional theranostic nanoplatforms. MPNs present unique properties, such as rapid preparation, negligible cytotoxicity, and pH responsiveness. Additionally, MPNs can be further modified and functionalized to meet specific application requirements. Here, the classification of polyphenols is first summarized, followed by the introduction of the properties and preparation strategies of MPNs. Then, their recent advances in biomedical sciences including bioimaging and anti-tumor therapies are highlighted. Finally, the main limitations, challenges, and outlooks regarding MPNs are raised and discussed.
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http://dx.doi.org/10.1002/smll.202100314DOI Listing
May 2021

The preliminary investigation of potential response biomarkers to PAHs exposure on childhood asthma.

J Expo Sci Environ Epidemiol 2021 May 10. Epub 2021 May 10.

The Key Laboratory of Modern Toxicology of Ministry of Education and Department of Health Inspection and Quarantine, Nanjing Medical University, Nanjing, China.

Background: Exposure to polycyclic aromatic hydrocarbons (PAHs) is a potential risk factor for asthma prevalence. This study aims to explore whether PAHs exposure is associated with childhood asthma by altering microbial diversity and metabolic profiles.

Methods: Thirty children with asthma and 30 children as control in Nanjing, China were recruited. Urinary 1-hydroxypyrene (1-OHPyr) level was determined by UPLC-Orbitrap-MS as a PAHs exposure biomarker. Logistic regression was conducted to investigate the association between 1-OHPyr and childhood asthma. Microbial diversity was analyzed by 16S rRNA gene sequencing. Metabolic profiles were obtained by UPLC-Orbitrap-MS methods. Differential microbiota and metabolites were screened and selected as response biomarkers or intermediates. Mediation analysis was conducted to assess the association between PAHs and asthma mediated by intermediates.

Results: Participating children with and without asthma aged 6.43 ± 2.23 years. The urinary 1-OHPyr level ranged from 0.10 to 1.51 μmol/mol (creatinine corrected) in the participants. The urinary 1-OHPyr level was associated with childhood asthma (OR = 7.21, 95% CI: 1.03-50.42 per 1 μmol/mol unit). Microbial diversity was decreased in the group with asthma and there was a significant shift in the abundance of Proteobacteria (at the phylum level), Veillonella and Prevotella (at the genus level). The enrichment pathway analysis showed that differentially expressed metabolites were involved in purine metabolism, amino acid metabolism, and lipid and fatty acid metabolism. The urinary 1-OHPyr level was associated with the abundance of Actinomyces sp. oral clone IO076 and 7-methylguanine that showed a mediation effect on the association between urinary 1-OHPyr levels and childhood asthma by mediation analysis.

Conclusions: Urinary 1-OHPyr exposure was associated with childhood asthma, microbial diversity, and metabolic profiles. Microbial diversity and metabolic profiles may be intermediates as response biomarkers to PAHs exposure in childhood asthma. Further research is needed to confirm these study results and determine the underlying mechanism.
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http://dx.doi.org/10.1038/s41370-021-00334-4DOI Listing
May 2021

Effect of AI Explanations on Human Perceptions of Patient-Facing AI-Powered Healthcare Systems.

J Med Syst 2021 May 4;45(6):64. Epub 2021 May 4.

The Institute of Software, Chinese Academy of Sciences, Beijing, China.

Ongoing research efforts have been examining how to utilize artificial intelligence technology to help healthcare consumers make sense of their clinical data, such as diagnostic radiology reports. How to promote the acceptance of such novel technology is a heated research topic. Recent studies highlight the importance of providing local explanations about AI prediction and model performance to help users determine whether to trust AI's predictions. Despite some efforts, limited empirical research has been conducted to quantitatively measure how AI explanations impact healthcare consumers' perceptions of using patient-facing, AI-powered healthcare systems. The aim of this study is to evaluate the effects of different AI explanations on people's perceptions of AI-powered healthcare system. In this work, we designed and deployed a large-scale experiment (N = 3,423) on Amazon Mechanical Turk (MTurk) to evaluate the effects of AI explanations on people's perceptions in the context of comprehending radiology reports. We created four groups based on two factors-the extent of explanations for the prediction (High vs. Low Transparency) and the model performance (Good vs. Weak AI Model)-and randomly assigned participants to one of the four conditions. Participants were instructed to classify a radiology report as describing a normal or abnormal finding, followed by completing a post-study survey to indicate their perceptions of the AI tool. We found that revealing model performance information can promote people's trust and perceived usefulness of system outputs, while providing local explanations for the rationale of a prediction can promote understandability but not necessarily trust. We also found that when model performance is low, the more information the AI system discloses, the less people would trust the system. Lastly, whether human agrees with AI predictions or not and whether the AI prediction is correct or not could also influence the effect of AI explanations. We conclude this paper by discussing implications for designing AI systems for healthcare consumers to interpret diagnostic report.
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http://dx.doi.org/10.1007/s10916-021-01743-6DOI Listing
May 2021

Retrieving Lab Test Related Questions from Social Q&A Sites by Combining Shallow Features and Deep Representations.

AMIA Annu Symp Proc 2020 25;2020:783-792. Epub 2021 Jan 25.

Florida state University, Tallahassee, FL, USA.

Patients face challenges in accurately interpreting their lab test results. To fulfill their knowledge gap, patients often turn to online resources, such as Community Question-Answering (CQA) sites, to seek meaningful information and support from their peers. Retrieving the most relevant information to patients' queries is important to help patients understand lab test results. However, few studies investigated the retrieval of lab test-related questions on CQA platforms. To address this research gap, we build and evaluate a system that automatically ranks questions about lab tests based on their similarity to a given question. The system is tested using diabetes-related questions collected from Yahoo! Answers' health section. Experimental results show that the regression-weighted combination of deep representations and shallow features was most effective in the Yahoo! Answers dataset. The proposed system can be extended to medical question retrieval, where questions contain a variety of lab tests.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075538PMC
June 2021

Patients' perceptions of using artificial intelligence (AI)-based technology to comprehend radiology imaging data.

Health Informatics J 2021 Apr-Jun;27(2):14604582211011215

Chinese Academy of Sciences, China.

Results of radiology imaging studies are not typically comprehensible to patients. With the advances in artificial intelligence (AI) technology in recent years, it is expected that AI technology can aid patients' understanding of radiology imaging data. The aim of this study is to understand patients' perceptions and acceptance of using AI technology to interpret their radiology reports. We conducted semi-structured interviews with 13 participants to elicit reflections pertaining to the use of AI technology in radiology report interpretation. A thematic analysis approach was employed to analyze the interview data. Participants have a generally positive attitude toward using AI-based systems to comprehend their radiology reports. AI is perceived to be particularly useful in seeking actionable information, confirming the doctor's opinions, and preparing for the consultation. However, we also found various concerns related to the use of AI in this context, such as cyber-security, accuracy, and lack of empathy. Our results highlight the necessity of providing AI explanations to promote people's trust and acceptance of AI. Designers of patient-centered AI systems should employ user-centered design approaches to address patients' concerns. Such systems should also be designed to promote trust and deliver concerning health results in an empathetic manner to optimize the user experience.
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http://dx.doi.org/10.1177/14604582211011215DOI Listing
April 2021

Propofol attenuates renal ischemia/reperfusion injury by regulating the MALAT1/miR-126-5p axis.

J Gene Med 2021 Apr 26:e3349. Epub 2021 Apr 26.

Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China.

Background: Propofol (PPF) plays a protective role in ischemia-reperfusion (I/R) in multiple organs, including renal ischemia-reperfusion injury (RIRI). This work is intended to investigate the underlying mechanisms by which PPF exerts its protective functions in RIRI.

Methods: BALB/c mice were employed for the construction of RIRI animal model. PPF pre-treatment was carried out before I/R. An in vitro I/R model was established with HK-2 cells after hypoxia/reoxygenation (H/R) culture, and PPF was utilized to treat the cells before H/R. qPCR was executed to detect long non-coding RNA MALAT1 and miR-126-5p expression levels. Flow cytometry was adopted to detect the apoptosis of HK-2 cells. Bioinformatics analysis, qPCR and a luciferase reporter gene experiment and a RNA immunoprecipitation experiment were used to determine the regulatory relationship between MALAT1 and miR-126-5p. The expression level of VEGFA was examined by Western blot.

Results: MALAT1 expression was augmented and miR-126-5p was decreased in RIRI models. PPF pre-treatment remarkably reduced creatinine and urea nitrogen levels in the serum of BALB/c mice with RIRI, and diminished the apoptosis of HK-2 cells treated with H/R. In addition, PPF pre-treatment markedly restrained the expression of MALAT1 in both in vivo and in vitro models and up-regulated miR-126-5p expression. MALAT1 could adsorb miR-126-5p to repress it and up-regulate VEGFA. MALAT1 overexpression reversed the protective effects of PPF on RIRI.

Conclusion: PPF protects the kidney against RIRI by inhibiting MALAT1 and up-regulating miR-126-5p expression, and indirectly inhibiting the expression of VEGFA.
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http://dx.doi.org/10.1002/jgm.3349DOI Listing
April 2021

Engineering a Hydrogen-Sulfide-Based Nanomodulator to Normalize Hyperactive Photothermal Immunogenicity for Combination Cancer Therapy.

Adv Mater 2021 Jun 25;33(22):e2008481. Epub 2021 Apr 25.

Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, SAR, 999078, China.

Photothermal therapy (PTT), one of the most-potent cancer therapeutic strategies known, is highlighted with excessive inflammatory response, while ablating cancer with immunogenic death. This hyperactive immune response may override PTT-triggered immunogenicity, exacerbate skin empyrosis, and incur permanent tissue injury and high-profile tumor regeneration. Therefore, an anticancer balance between pathological and protective immune response is urgently needed for an advanced photothermal therapeutic tactic. Herein, a gas-modulated photothermal immunogenicity strategy is proposed by integrating an amphiphilic-conjugated polymer with a polysulfide-based hydrogen sulfide (H S) donor (2,2'-dipyridyl [email protected]) (where CP = conjugated polymer and PEG = poly(ethylene glycol)). The CP is endowed with NIR-II fluorescence capacity and favorable photothermal effect, tracing the tumor for precise therapeutics. The polysulfide donor can release H S triggered by intracellular glutathione, which elicits mitochondrial dysfunction and robust anti-inflammation effect. Ultimately, this gas-modulated PTT strategy inhibits tumor growth remarkably and limits the magnitude of PTT-induced proinflammatory tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1β) cytokines. Moreover, the regulated inflammation accelerates PTT-induced wound healing. A H S-modulated PTT with adaptive immune response is thus recommended as an advanced strategy to cancer therapeutics.
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http://dx.doi.org/10.1002/adma.202008481DOI Listing
June 2021

IL-24 inhibits the malignancy of human glioblastoma cells via destabilization of Zeb1.

Biol Chem 2021 Jun 26;402(7):839-848. Epub 2021 Apr 26.

Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin150001, People's Republic of China.

Glioblastoma (GBM) is the most common and fatal type of primary malignant tumours in the central nervous system. Cytokines such as interleukins (ILs) play an important role in GBM progression. Our present study found that IL-24 is down-regulated in GBM cells. Recombinant IL-24 (rIL-24) can suppress the migration and invasion of GBM cells while increase its chemo-sensitivity to temozolomide (TMZ) treatment. rIL-24 negatively regulates the expression of Zeb1, one well known transcription factors of epithelial to mesenchymal transition (EMT) of cancer cells. Over expression of Zeb1 can attenuate IL-24-suppressed malignancy of GBM cells. Mechanistically, IL-24 decreases the protein stability of Zeb1 while has no effect on its mRNA stability. It is due to that IL-24 can increase the expression of FBXO45, which can destabilize Zeb1 in cancer cells. Collectively, we reveal that IL-24 can suppress the malignancy of GBM cells via decreasing the expression of Zeb1. It suggests that targeted activation of IL-24 signals might be a potential therapy approach for GBM treatment.
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http://dx.doi.org/10.1515/hsz-2020-0373DOI Listing
June 2021

27-Hydroxycholesterol is a specific factor in the neoplastic microenvironment of HCC that causes MDR via GRP75 regulation of the redox balance and metabolic reprogramming.

Cell Biol Toxicol 2021 Apr 20. Epub 2021 Apr 20.

The Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.

Objective: Due to the tissue specificity of the liver, long-term exposure to a high concentration of 27-hydroxycholesterol (27HC) is a special characteristic of the tumour microenvironment in hepatocellular carcinoma (HCC). However, what occurs after HCC cells are long-term exposure to 27HC and the molecular mechanisms involved remain largely unexamined.

Methods: A long-term 27HC-treated HepG2 cell line and the xenografts in nude mice were used as experimental models. Molecular mechanisms were investigated using bioinformatics analysis and molecular biological experiments.

Results: Here, we found that by inducing an increase in oxidative stress signalling, 27HC activated glucose-regulated protein 75 (GRP75). On the one hand, GRP75 resulted in a change in the redox balance by regulating ROS generation and antioxidant system activity via affecting MMP, NRF2, HO-1, and NQO1 levels. On the other hand, GRP75 modified the metabolic reprogramming process by regulating key factors (HIF-1α, p-Akt, and c-myc) and glucose uptake, facilitating HCC cell growth in the inhospitable microenvironment. These two factors caused HCC cells to resist 27HC-induced cytotoxicity and attain multidrug resistance (MDR).

Conclusions: Our present study not only identified 27HC, a characteristic component of the neoplastic microenvironment of HCC that causes MDR via GRP75 to regulate the redox balance and metabolic reprogramming, but also revealed that targeted intervention by the "switch"-like molecule GRP75 could reverse the effect of 27HC from cancer promotion to cytotoxicity in HCC, suggesting a new strategy for specific intervention of HCC.
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http://dx.doi.org/10.1007/s10565-021-09607-yDOI Listing
April 2021

Correction to: The Preliminary Study on the Association Between PAHs and Air Pollutants and Microbiota Diversity.

Arch Environ Contam Toxicol 2021 Apr;80(3):659

The Key Laboratory of Modern Toxicology of Ministry of Education and Department of Health Inspection and Quarantine, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.

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http://dx.doi.org/10.1007/s00244-021-00822-6DOI Listing
April 2021

Minocycline alleviates peripheral nerve adhesion by promoting regulatory macrophage polarization via the TAK1 and its downstream pathway.

Life Sci 2021 Jul 27;276:119422. Epub 2021 Mar 27.

Department of Hand Surgery, China-Japan Union Hospital of Jilin University, No. 126 Xiantai Street, Changchun 130033, PR China. Electronic address:

Aims: Inflammation plays a key role in peripheral nerve adhesion and often leads to severe pain and nerve dysfunction. Minocycline was reported to have potent anti-inflammatory effects and might be a promising drug to prevent or attenuate peripheral nerve adhesion. The present study aimed to clarify whether minocycline contributes to nerve adhesion protection and its underlying mechanism.

Materials And Methods: Rats with sciatic nerve adhesion induced by glutaraldehyde glue (GG) were intraperitoneally injected with minocycline or saline every 12 h for 7 consecutive days. After that, the adhesion score, Ashcroft score, demyelination, macrophage polarization and inflammatory factors in peripheral nerve adhesion tissues or tissues in sham group were determined with histological staining, western blot and real time-PCR. Murine macrophage RAW264.7 cells were stimulated by LPS alone or together with minocycline at different concentrations and time duration to study the mechanism of minocycline in alleviating nerve adhesion.

Key Findings: We found that minocycline treatment reduced the adhesion score, Ashcroft score, the growth of scar tissue, demyelination, and macrophage recruitment. Moreover, minocycline significantly and dose-dependently promoted regulatory macrophage polarization but decreased pro-inflammatory macrophage polarization. Furthermore, mechanism studies showed that TAK1 and its downstream pathway p38/JNK/ERK1/2/p65 were inhibited by minocycline, which led to lower IL-1β and TNFα expression, but increased IL-10 expression.

Significance: Altogether, these results suggest that minocycline is highly effective against peripheral nerve adhesion through anti-fibrosis, anti-inflammation, and myelination protection, making it a highly promising candidate for treating adhesion-related disorders.
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http://dx.doi.org/10.1016/j.lfs.2021.119422DOI Listing
July 2021

Distinction between vaginal and cervical microbiota in high-risk human papilloma virus-infected women in China.

BMC Microbiol 2021 Mar 25;21(1):90. Epub 2021 Mar 25.

The Gynecology Department of Beijing Obstetrics and Gynecology Hospital, Capital Medical University, No. 251 of Yaojiayuan Road, Chaoyang District, Beijing, China.

Background: High-risk human papilloma virus (hrHPV) is the main causal factor of cervical precancer and cancer when persistent infection is left untreated. Previous studies have confirmed the vaginal microbiota is associated with HPV infection and the development of cervical lesions. The microbiota at different parts of the female genital tract is closely related but different from each other. To analyze the distinction between the vaginal and cervical microbiota of hrHPV(+) women in China, one hundred subjects were recruited, including 10 patients with HPV16/18(+) and cervical carcinoma, 38 patients with HPV16/18(+) but no cervical carcinoma, 32 patients with other hrHPV(+) and 20 healthy controls with HPV(-). Vaginal and cervical microbiota were separately tested through next-generation sequencing (NGS) targeting the variable region (V3-V4) of the bacterial ribosome 16S rRNA gene.

Results: HrHPV(+) subjects had higher percentages of vaginal douching history (P = 0.001), showed more frequent usage of sanitary pads (P = 0.007), had more sex partners (P = 0.047), were more sexually active (P = 0.025) and more diversed in ways of contraception (P = 0.001). The alpha diversity of the cervical microbiota was higher than that of the vagina. The cervical microbiota consisted of a lower percentage of Firmicutes and a higher percentage of Proteobacteria than the vagina at the phylum level. Sphingomonas, belonging to α-Proteobacteria, was almost below the detection limit in the vagina but accounted for five to 10 % of the bacteria in the hrHPV(-) cervix (P<0.001) and was inversely associated with hrHPV infection (P<0.05). Pseudomonas, belonging to γ-Proteobacteria, could hardly be seen in the normal vagina and shared a small percentage in the normal cervix but was significantly higher in the HPV16/18(+) (P<0.001) and cancerous cervix (P<0.05). No significant difference was shown in the percentage of BV associated anaerobes, like Gardnerella, Prevotella, Atopobium and Sneathia, between the cevix and vigina.

Conclusions: The proportion of Proteobacteria was significantly higher in the cervical microbiota than that of vagina. The hrHPV infection and cervical cancer was positively associated with Pseudomonas and negatively associated with Sphingomonas. It is of great improtance to deeply explore the cervical microbiota and its function in cervical cacinogenesis.
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http://dx.doi.org/10.1186/s12866-021-02152-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993496PMC
March 2021

Effects of Lyophilization on the Release Profiles of 3D Printed Delivery Systems Fabricated with Carboxymethyl Cellulose Hydrogel.

Polymers (Basel) 2021 Feb 28;13(5). Epub 2021 Feb 28.

Department of Industrial and Manufacturing Systems Engineering, Iowa State University, Ames, IA 50011, USA.

Recently, increasing numbers of researchers are becoming interested in 3D bioprinting because it provides customizability and structural complexity, which is difficult for traditional subtractive manufacturing to achieve. One of the most critical factors in bioprinting is the material. Depending on the bio-applications, materials should be bio-inert or bio-active, non-toxic, and along with those characteristics, mechanical properties should also meet the applicational or manufacturing requirement. As previously validated for bioprinting, carboxymethyl cellulose (CMC) hydrogel is focused on the printability and release control test in this study. With a differentiated weight percentage of CMC hydrogels were used to 3D print capsules filled with food degradable colorant at designated voids to mimic capsules manufactured for oral delivery. Standard USP (United States Pharmacopeia) dissolution apparatus II (Paddle) evaluations were performed both on lyophilized and non-lyophilized printed capsules. The first-order model was selected due to high linear fitting regression. Upon 24 h dissolution, non-lyophilized capsules showed a different release efficiency when the CMC percentage varied, while lyophilized capsules showed no significant difference. This study signifies the possibility of customizing oral drug delivery by printing capsules with CMC hydrogel. The improved delivery efficiency demonstrated by capsules with post-process lyophilizing proposed potential optimization options for pharmaceutical manufacturing industries.
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http://dx.doi.org/10.3390/polym13050749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957655PMC
February 2021

Attention Mechanism with BERT for Content Annotation and Categorization of Pregnancy-Related Questions on a Community Q&A Site.

Proceedings (IEEE Int Conf Bioinformatics Biomed) 2020 Dec 13;2020:1077-1081. Epub 2021 Jan 13.

School of Information, Florida State University, Tallahassee, USA.

In recent years, the social web has been increasingly used for health information seeking, sharing, and subsequent health-related research. Women often use the Internet or social networking sites to seek information related to pregnancy in different stages. They may ask questions about birth control, trying to conceive, labor, or taking care of a newborn or baby. Classifying different types of questions about pregnancy information (e.g., before, during, and after pregnancy) can inform the design of social media and professional websites for pregnancy education and support. This research aims to investigate the attention mechanism built-in or added on top of the BERT model in classifying and annotating the pregnancy-related questions posted on a community Q&A site. We evaluated two BERT-based models and compared them against the traditional machine learning models for question classification. Most importantly, we investigated two attention mechanisms: the built-in self-attention mechanism of BERT and the additional attention layer on top of BERT for relevant term annotation. The classification performance showed that the BERT-based models worked better than the traditional models, and BERT with an additional attention layer can achieve higher overall precision than the basic BERT model. The results also showed that both attention mechanisms work differently on annotating relevant content, and they could serve as feature selection methods for text mining in general.
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http://dx.doi.org/10.1109/bibm49941.2020.9313379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929090PMC
December 2020

Oxygen-Enriched Metal-Phenolic X-Ray Nanoprocessor for Cancer Radio-Radiodynamic Therapy in Combination with Checkpoint Blockade Immunotherapy.

Adv Sci (Weinh) 2021 Feb 31;8(4):2003338. Epub 2020 Dec 31.

Cancer Center Faculty of Health Sciences University of Macau Macau SAR, 999078 China.

Radiotherapy (RT) based on DNA damage and reactive oxygen species (ROS) generation has been clinically validated in various types of cancer. However, high dose-dependent induced toxicity to tissues, non-selectivity, and radioresistance greatly limit the application of RT. Herein, an oxygen-enriched X-ray nanoprocessor [email protected] nanoparticle is developed for improving the therapeutic effect of RT-radiodynamic therapy (RDT), enhancing modulation of hypoxia tumor microenvironment (TME) and promoting antitumor immune response in combination with programmed cell death protein 1 (PD-1) immune checkpoint blockade. All functional molecules are integrated into the nanoparticle based on metal-phenolic coordination, wherein one high-Z radiosensitizer (hafnium, Hf) coordinated with chlorin e6 (Ce6) modified polyphenols and a promising oxygen carrier (hemoglobin, Hb) is encapsulated for modulation of oxygen balance in the hypoxia TME. Specifically, under single X-ray irradiation, radioluminescence excited by Hf can activate photosensitizer Ce6 for ROS generation by RDT. Therefore, this combinatory strategy induces comprehensive antitumor immune response for cancer eradication and metastasis inhibition. This work presents a multifunctional metal-phenolic nanoplatform for efficient X-ray mediated RT-RDT in combination with immunotherapy and may provide a new therapeutic option for cancer treatment.
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http://dx.doi.org/10.1002/advs.202003338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887592PMC
February 2021

Schisandrin B for the treatment of male infertility.

Clin Transl Med 2021 Feb;11(2):e333

State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Maolecular Pharmaceutics and New Drug System, and Scool of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.

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http://dx.doi.org/10.1002/ctm2.333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901724PMC
February 2021

Comparative analysis of the vaginal microbiome of Chinese women with Trichomonas vaginalis and mixed infection.

Microb Pathog 2021 May 16;154:104790. Epub 2021 Feb 16.

Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.

The high prevalence and serious long-term sequelae of Trichomonas vaginalis (TV) infection worldwide is of a particular concern; however, data regarding the differences in the composition of the vaginal microbiome in cases of single TV infection or mixed infections (i.e., presence of TV and bacterial vaginosis) are scarce. We employed metagenomic sequencing analyses to study gene expression in the vaginal microbiota of women with single TV infection and mixed infection. Women infected with only TV had significantly higher abundance of Mycoplasma, Prevotella, and Streptococcus compared to women without vaginal infection (control). Women infected with mixed infections had a significantly higher abundance of Mycoplasma, Prevotella, Streptococcus, Anaerococcus, Dialister, Peptostreptococcus, Peptoniphilus and a significantly lower abundance of Lactobacillus than TV alone. Mixed infections had a significantly higher abundance of Prevotella, Anaerococcus and Dialister. Our findings suggest that the bacterial community composition varies among healthy women, women with TV alone, and those with mixed infection, and we hypothesize that these bacterial vaginosis (BV)-associated bacterium may play a role in the pathogenesis and recurrence of TV. Probiotic pessaries may necessarily be the answer because shifting the vaginal microbiome and host responses is probably a complex undertaking.
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http://dx.doi.org/10.1016/j.micpath.2021.104790DOI Listing
May 2021

Doubly N-confused phlorin and phlorinone analogue.

Chem Commun (Camb) 2021 Mar;57(22):2772-2775

Key Laboratory of Catalysis and Energy Materials Chemistry of Ministry of Education & Hubei Key Laboratory of Catalysis and Materials Science, South-Central University for Nationalities, Wuhan 430074, China.

A doubly N-confused phlorin and phlorinone analogue were synthesized from a β,β'-linked dipyrromethane precursor and characterized by means of NMR and UV-Vis spectroscopies, X-ray crystallography, and electrochemistry. Solvents have a considerable impact on the optical absorption of the doubly N-confused phlorin so that it can differentiate simple alcohols such as methanol and ethanol.
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http://dx.doi.org/10.1039/d1cc00216cDOI Listing
March 2021

Nanostructure of Functional Larotaxel Liposomes Decorated with Guanine-Rich Quadruplex Nucleotide-Lipid Derivative for Treatment of Resistant Breast Cancer.

Small 2021 Apr 31;17(13):e2007391. Epub 2021 Jan 31.

State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.

Breast cancer is the most common malignant disease in women all over the world and its chemotherapy outcome is restricted by multidrug resistance. Here, a nanostructure by functional larotaxel liposomes decorated with guanine-rich quadruplex nucleotide-lipid derivative for treatment of resistant breast cancer is developed. The studies are performed on the resistant breast cancer cells and the cancer-bearing mice. The nucleotide-lipid derivative (DSPE-PEG -C -GT28nt) is synthesized by introducing a hydrophobic hexyl linkage between GT-28nt (containing 17 guanines and 11 thymidines) and DSPE-PEG -NHS, and is incorporated on the functional larotaxel liposomes for specific binding with nucleolin receptor on the resistant cancer cells. The studies demonstrate that the liposomes had long circulatory effect, targeted capability, and significant anticancer efficacy in resistant cancer-bearing mice. The studies further reveal their action mechanism, consisting of blocking depolymerization of microtubules, arresting cell cycle, blocking JAK-STAT signaling pathway, and inhibiting activity of antiapoptotic proteins. In conclusion, the functional larotaxel liposomes can be used for effective treatment of drug-resistant breast cancer, and this study also offers a novel targeted nanomedicine based on nucleotide-lipid derivative.
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http://dx.doi.org/10.1002/smll.202007391DOI Listing
April 2021

Silencing long non-coding RNA HNF1A-AS1 inhibits growth and resistance to TAM of breast cancer cells via the microRNA-363/SERTAD3 axis.

J Drug Target 2021 May 17:1-12. Epub 2021 May 17.

Third Affiliated Hospital of Zhengzhou University (Henan Maternal and Child Health Care Hospital), Zhengzhou, Henan, P.R. China.

Long non-coding RNAs (lncRNAs) can exert effects on drug resistance of cancer cells. This study investigated the role of lncRNA HNF1A-antisense 1 (HNF1A-AS1) in growth and Tamoxifen (TAM) sensitivity of breast cancer (BC) cells. HNF1A-AS1 expression was promoted in BC cells and tissues. BC cells with HNF1A-AS1 silencing were constructed to detect cell proliferation. TAM resistant cell line with HNF1A-AS1 silencing and parent cell line with overexpressed HNF1A-AS1 were constructed to measure drug resistance. Silencing HNF1A-AS1 reduced proliferation and TAM resistance of BC cells. The downstream microRNAs (miRs) of HNF1A-AS1 and its targets were figured out and their functions in TAM resistance of BC cells were identified. HNF1A-AS1 sponged miR-363 to promote SERTAD3 expression. Downregulation of miR-363 or upregulation of SERTAD3 stimulated TAM resistance of BC cells. The findings were reproduced in experiments. It could be concluded that silencing HNF1A-AS1 inhibited growth and drug resistance to TAM of BC cells through the miR-363/SERTAD3 axis and the inactivation of the TGF-β/Smad pathway.
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http://dx.doi.org/10.1080/1061186X.2021.1878362DOI Listing
May 2021

Pyridazine-bridged expanded rosarin and semi-rosarinogen.

Chem Commun (Camb) 2021 Feb;57(12):1486-1489

Key Laboratory of Catalysis and Energy Materials Chemistry of Ministry of Education & Hubei Key Laboratory of Catalysis and Materials Science, South-Central University for Nationality, Wuhan, Hubei 430074, China.

The synthesis of the pyridazine-bridged expanded rosarin 1 and a reduced precursor, semi-rosarinogen 2, is reported. A single crystal X-ray diffraction analysis of 1 and theoretical calculations show that both 1 and 2 have distorted structures. Expanded rosarin 1 and its precursor 2 can differentiate various thiols in organic solvents by means of species-specific colour changes and reaction times.
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http://dx.doi.org/10.1039/d0cc07433kDOI Listing
February 2021

The novel three-dimensional pulse images analyzed by dynamic L-cube polynomial model.

Med Biol Eng Comput 2021 Feb 12;59(2):315-326. Epub 2021 Jan 12.

School of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.

A dynamic L-cube polynomial is proposed to analyze dynamic three-dimensional pulse images (d3DPIs), as an extension of the previous static L-cube polynomial. In this paper, a weighted least squares (WLS) method is proposed to fit the amplitude C(t) of d3DPI at four physiological key points in addition to the best fit of L-cube polynomials to the measured normal and cold-pressor-test (CPT)-induced taut 3DPIs. Compared with other two fitting functions, C(t) of a dynamic L-cube polynomial can be well matched by the proposed WLS method with the least relative error at four physiological key points in one beat with statistical significance, in addition to the best fit of the measured 3DPIs. Therefore, a dynamic L-cube polynomial can reflect dynamic time characteristics of normal and CPT-induced hypertensive taut 3DPIs, which can be used as an evidence of hypertension diagnosis.
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http://dx.doi.org/10.1007/s11517-020-02289-4DOI Listing
February 2021

Phenolic immunogenic cell death nanoinducer for sensitizing tumor to PD-1 checkpoint blockade immunotherapy.

Biomaterials 2021 02 30;269:120638. Epub 2020 Dec 30.

Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China; Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China. Electronic address:

A critical challenge remains in PD-1 checkpoint blockade immunotherapy is few tumor specific T cells infiltration in hypoxic tumor microenvironment (TME). Improving immunogenic cell death (ICD) associated immunogenicity can make tumor sensitive to PD-1 checkpoint blockade immunotherapy. Herein, a phenolic ICD inducer was engineered by self-assembly of the superior ICD inducer (doxorubicin, DOX), phenolic manganese dioxide nanoreactor, ferric iron and PEG-polyphenols (MDP NPs) via metal phenolic coordination. These oxygen self-supporting MDP NPs strengthen DOX based ROS-dependent cell death and their metal mediated chemodynamic effect accelerate ICD induction. Together with concomitant ICD triggered by DOX, MDP NPs successively lead to tumor-associated antigen boosting, DCs maturation and ultimately enhance tumor-specific T cells infiltration. Furthermore, MDP NPs efficiently modulated hypoxic TME for effective macrophages recruitment. This promising ICD-augment strategy efficiently improve tumor response to PD-1 checkpoint blockade immunotherapy, resulting in a significant antitumor immune response in primary tumor and a strong abscopal effect to distant tumor. Our simple and versatile phenolic inducer expands the application of chemodrugs based ICD enhancing PD-1 checkpoint blockade immunotherapy.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120638DOI Listing
February 2021

Inhibition of autophagy by 3-methyladenine restricts murine cytomegalovirus replication.

J Med Virol 2021 Jan 9. Epub 2021 Jan 9.

Department of Pediatrics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China.

Cytomegalovirus (CMV) induced autophagy affects virus replication and survival of the infected cells. The purpose of this study was to investigate the role of autophagy inhibition by 3-methyladenine (3-MA) on murine cytomegalovirus (MCMV) replication and whether it is associated with caspase-3 dependent apoptosis. The eyecup isolated from adult C57BL/6J mice (6-8 weeks old) and mouse embryo fibroblast cells (MEFs) were infected with MCMV K181 strain, followed by the treatment of 3-methyladenine (3-MA), chloroquine, or rapamycin to block or stimulate autophagy. In cultured MEFs, the ratio of LC3I/II was reduced at 24 hours post infection (hpi), but was increased at 48 hpi In the eyecup culture, LC3I/II ratio was also decreased at 4 and 7 days post infection (dpi). In addition, caspase-3 cleavage was increased at 48 hpi in MEFs and also elevated in MCMV infected eyecups at 4, 7, 10, and 14 dpi. 3-MA treatment significantly inhibited the virus replication in MEFs and eyecups. The expression of early antigen (EA) of MCMV was also decreased in MEFs and eyecups. Meanwhile, cleaved caspase-3 dependent cell death was promoted with the presence of 3-MA in MCMV infected MEFs and eyecups, while RIPK1/RIPK3/MLKL pathway was inhibited by 3-MA in eyecups. Inhibition of autophagy by 3-MA restricts virus replication and promotes caspase-3 dependent apoptosis in the eyecup and MEFs with MCMV infection. It can be explained that during the early period of MCMV infection, the suppressed autophagy process directly reduced virus release, but later caspase-3 dependent apoptosis dominated and resulted in decreased virus replication.
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http://dx.doi.org/10.1002/jmv.26787DOI Listing
January 2021

Utilization of Self-Diagnosis Health Chatbots in Real-World Settings: Case Study.

J Med Internet Res 2021 01 6;23(1):e19928. Epub 2021 Jan 6.

The Institute of Software, Chinese Academy of Sciences, Beijing, China.

Background: Artificial intelligence (AI)-driven chatbots are increasingly being used in health care, but most chatbots are designed for a specific population and evaluated in controlled settings. There is little research documenting how health consumers (eg, patients and caregivers) use chatbots for self-diagnosis purposes in real-world scenarios.

Objective: The aim of this research was to understand how health chatbots are used in a real-world context, what issues and barriers exist in their usage, and how the user experience of this novel technology can be improved.

Methods: We employed a data-driven approach to analyze the system log of a widely deployed self-diagnosis chatbot in China. Our data set consisted of 47,684 consultation sessions initiated by 16,519 users over 6 months. The log data included a variety of information, including users' nonidentifiable demographic information, consultation details, diagnostic reports, and user feedback. We conducted both statistical analysis and content analysis on this heterogeneous data set.

Results: The chatbot users spanned all age groups, including middle-aged and older adults. Users consulted the chatbot on a wide range of medical conditions, including those that often entail considerable privacy and social stigma issues. Furthermore, we distilled 2 prominent issues in the use of the chatbot: (1) a considerable number of users dropped out in the middle of their consultation sessions, and (2) some users pretended to have health concerns and used the chatbot for nontherapeutic purposes. Finally, we identified a set of user concerns regarding the use of the chatbot, including insufficient actionable information and perceived inaccurate diagnostic suggestions.

Conclusions: Although health chatbots are considered to be convenient tools for enhancing patient-centered care, there are issues and barriers impeding the optimal use of this novel technology. Designers and developers should employ user-centered approaches to address the issues and user concerns to achieve the best uptake and utilization. We conclude the paper by discussing several design implications, including making the chatbots more informative, easy-to-use, and trustworthy, as well as improving the onboarding experience to enhance user engagement.
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http://dx.doi.org/10.2196/19928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817366PMC
January 2021

Phytochrome B inhibits darkness-induced hypocotyl adventitious root formation by stabilizing IAA14 and suppressing ARF7 and ARF19.

Plant J 2021 Mar 28;105(6):1689-1702. Epub 2021 Jan 28.

National Key Laboratory of Plant Molecular Genetics, Chinese Academy of Sciences Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, 200032, China.

Adventitious roots (ARs) are an important root type for plants and display a high phenotypic plasticity in response to different environmental stimuli. Previous studies found that dark-light transition can trigger AR formation from the hypocotyl of etiolated Arabidopsis thaliana, which was used as a model for the identification of regulators of AR biogenesis. However, the central regulatory machinery for darkness-induced hypocotyl AR (HAR) remains elusive. Here, we report that photoreceptors suppress HAR biogenesis through regulating the molecular module essential for lateral roots. We found that hypocotyls embedded in soil or in continuous darkness are able to develop HARs, wherein photoreceptors act as negative regulators. Distinct from wound-induced ARs that require WOX11 and WOX12, darkness-induced HARs are fully dependent on ARF7, ARF19, WOX5/7, and LBD16. Further studies established that PHYB interacts with IAA14, ARF7, and ARF9. The interactions stabilize IAA14 and inhibit the transcriptional activities of ARF7 and ARF19 and thus suppress biogenesis of darkness-induced HARs. This finding not only revealed the central machinery controlling HAR biogenesis but also illustrated that AR formation could be initiated by multiple pathways.
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http://dx.doi.org/10.1111/tpj.15142DOI Listing
March 2021