Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Serum Amyloid A3 Fuels a Feed-Forward Inflammatory Response to the Bacterial Amyloid Curli in the Enteric Nervous System","authors":"Peter Verstraelen ,&nbsp;Samuel Van Remoortel ,&nbsp;Nouchin De Loose ,&nbsp;Rosanne Verboven ,&nbsp;Gerardo Garcia-Diaz Barriga ,&nbsp;Anne Christmann ,&nbsp;Manuela Gries ,&nbsp;Shingo Bessho ,&nbsp;Jing Li ,&nbsp;Carmen Guerra ,&nbsp;Çagla Tükel ,&nbsp;Sales Ibiza Martinez ,&nbsp;Karl-Herbert Schäfer ,&nbsp;Jean-Pierre Timmermans ,&nbsp;Winnok H. De Vos","doi":"10.1016/j.jcmgh.2024.03.013","DOIUrl":"10.1016/j.jcmgh.2024.03.013","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Mounting evidence suggests the gastrointestinal microbiome is a determinant of peripheral immunity and central neurodegeneration, but the local disease mechanisms remain unknown. Given its potential relevance for early diagnosis and therapeutic intervention, we set out to map the pathogenic changes induced by bacterial amyloids in the gastrointestinal tract and its enteric nervous system.</p></div><div><h3>Methods</h3><p>To examine the early response, we challenged primary murine myenteric networks with curli, the prototypical bacterial amyloid, and performed shotgun RNA sequencing and multiplex enzyme-linked immunosorbent assay. Using enteric neurosphere-derived glial and neuronal cell cultures, as well as in vivo curli injections into the colon wall, we further scrutinized curli-induced pathogenic pathways.</p></div><div><h3>Results</h3><p>Curli induced a proinflammatory response, with strong up-regulation of <em>Saa3</em> and the secretion of several cytokines. This proinflammatory state was induced primarily in enteric glia, was accompanied by increased levels of DNA damage and replication, and triggered the influx of immune cells <em>in vivo</em>. The addition of recombinant Serum Amyloid A3 (SAA3) was sufficient to recapitulate this specific proinflammatory phenotype while <em>Saa3</em> knock-out attenuated curli-induced DNA damage and replication. Similar to curli, recombinant SAA3 caused a strong up-regulation of <em>Saa3</em> transcripts, illustrating its self-amplifying potential . Since colonization of curli-producing <em>Salmonella</em> and dextran sulfate sodium–induced colitis triggered a significant increase in <em>Saa3</em> transcripts as well, we assume SAA3plays a central role in enteric dysfunction. Inhibition of dual leucine zipper kinase, an upstream regulator of the c-Jun N-terminal kinase pathway responsible for SAA3 production, attenuated curli- and recombinant SAA3-induced <em>Saa3</em> up-regulation, DNA damage, and replication in enteric glia.</p></div><div><h3>Conclusions</h3><p>Our results position SAA3 as an important mediator of gastrointestinal vulnerability to bacterial-derived amyloids and demonstrate the potential of dual leucine zipper kinase inhibition to dampen enteric pathology.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000687/pdfft?md5=13e90bab07a334e99822608e520cee7f&pid=1-s2.0-S2352345X24000687-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140332314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammation in Alcohol-Associated Hepatitis: Pathogenesis and Therapeutic Targets","authors":"Dechun Feng ,&nbsp;Seonghwan Hwang ,&nbsp;Adrien Guillot ,&nbsp;Yang Wang ,&nbsp;Yukun Guan ,&nbsp;Cheng Chen ,&nbsp;Luca Maccioni ,&nbsp;Bin Gao","doi":"10.1016/j.jcmgh.2024.04.009","DOIUrl":"10.1016/j.jcmgh.2024.04.009","url":null,"abstract":"<div><p>Alcohol-associated hepatitis (AH) is an acute-on-chronic liver injury that occurs in patients with chronic alcohol-associated liver disease (ALD). Patients with severe AH have high short-term mortality and lack effective pharmacologic therapies. Inflammation is believed to be one of the key factors promoting AH progression and has been actively investigated as therapeutic targets over the last several decades, but no effective inflammatory targets have been identified so far. In this review, we discuss how inflammatory cells and the inflammatory mediators produced by these cells contribute to the development and progression of AH, with focus on neutrophils and macrophages. The crosstalk between inflammatory cells and liver nonparenchymal cells in the pathogenesis of AH is elaborated. We also deliberate the application of recent cutting-edge technologies in characterizing liver inflammation in AH. Finally, the potential therapeutic targets of inflammatory mediators for AH are briefly summarized.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001061/pdfft?md5=ac58214335ea3ec42413d467c16df3bd&pid=1-s2.0-S2352345X24001061-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140869550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protease-Induced Excitation of Dorsal Root Ganglion Neurons in Response to Acute Perturbation of the Gut Microbiota Is Associated With Visceral and Somatic Hypersensitivity","authors":"","doi":"10.1016/j.jcmgh.2024.03.006","DOIUrl":"10.1016/j.jcmgh.2024.03.006","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Abdominal pain is a major symptom of diseases that are associated with microbial dysbiosis, including irritable bowel syndrome and inflammatory bowel disease. Germ-free mice are more prone to abdominal pain than conventionally housed mice, and reconstitution of the microbiota in germ-free mice reduces abdominal pain sensitivity. However, the mechanisms underlying microbial modulation of pain remain elusive. We hypothesized that disruption of the intestinal microbiota modulates the excitability of peripheral nociceptive neurons.</p></div><div><h3>Methods</h3><p>In vivo and in vitro assays of visceral sensation were performed on mice treated with the nonabsorbable antibiotic vancomycin (50 μg/mL in drinking water) for 7 days and water-treated control mice. Bacterial dysbiosis was verified by 16s rRNA analysis of stool microbial composition.</p></div><div><h3>Results</h3><p>Treatment of mice with vancomycin led to an increased sensitivity to colonic distension in vivo and in vitro and hyperexcitability of dorsal root ganglion (DRG) neurons in vitro<em>,</em> compared with controls. Interestingly, hyperexcitability of DRG neurons was not restricted to those that innervated the gut, suggesting a widespread effect of gut dysbiosis on peripheral pain circuits. Consistent with this, mice treated with vancomycin were more sensitive than control mice to thermal stimuli applied to hind paws. Incubation of DRG neurons from naive mice in serum from vancomycin-treated mice increased DRG neuron excitability, suggesting that microbial dysbiosis alters circulating mediators that influence nociception. The cysteine protease inhibitor E64 (30 nmol/L) and the protease-activated receptor 2 (PAR-2) antagonist GB-83 (10 μmol/L) each blocked the increase in DRG neuron excitability in response to serum from vancomycin-treated mice, as did the knockout of PAR-2 in NaV1.8-expressing neurons. Stool supernatant, but not colonic supernatant, from mice treated with vancomycin increased DRG neuron excitability via cysteine protease activation of PAR-2.</p></div><div><h3>Conclusions</h3><p>Together, these data suggest that gut microbial dysbiosis alters pain sensitivity and identify cysteine proteases as a potential mediator of this effect.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000584/pdfft?md5=8c9b95d3dd80a13cc657418d06757cec&pid=1-s2.0-S2352345X24000584-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140144711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Kids on the Block: Immature Myeloid Cells in Intestinal Regeneration","authors":"Vik Meadows,&nbsp;Nan Gao","doi":"10.1016/j.jcmgh.2023.11.011","DOIUrl":"10.1016/j.jcmgh.2023.11.011","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X23002102/pdfft?md5=f7d26cf6ee70c0529d9c935b865c694e&pid=1-s2.0-S2352345X23002102-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138489215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TOC","authors":"","doi":"10.1016/S2352-345X(23)00224-2","DOIUrl":"https://doi.org/10.1016/S2352-345X(23)00224-2","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X23002242/pdfft?md5=6543da2703ddee09e39965a70aa26951&pid=1-s2.0-S2352345X23002242-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139479976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover","authors":"","doi":"10.1016/S2352-345X(24)00140-1","DOIUrl":"10.1016/S2352-345X(24)00140-1","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001401/pdfft?md5=d160c5f1dc6e5bd0541edd6f016a7fd4&pid=1-s2.0-S2352345X24001401-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141993059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatocyte-specific Epidermal Growth Factor Receptor Deletion Promotes Fibrosis but has no Effect on Steatosis in Fast-food Diet Model of Metabolic Dysfunction-associated Steatotic Liver Disease","authors":"","doi":"10.1016/j.jcmgh.2024.101380","DOIUrl":"10.1016/j.jcmgh.2024.101380","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most prevalent chronic liver disorder, with no approved treatment. Our previous work demonstrated the efficacy of a pan-ErbB inhibitor, Canertinib, in reducing steatosis and fibrosis in a murine fast-food diet (FFD) model of MASLD. The current study explores the effects of hepatocyte-specific ErbB1 (ie, epidermal growth factor receptor [EGFR]) deletion in the FFD model.</p></div><div><h3>Methods</h3><p>EGFR^flox/flox mice, treated with AAV8-TBG-CRE to delete EGFR specifically in hepatocytes (EGFR-KO), were fed either a chow-diet or FFD for 2 or 5 months.</p></div><div><h3>Results</h3><p>Hepatocyte-specific EGFR deletion reduced serum triglyceride levels but did not prevent steatosis. Surprisingly, hepatic fibrosis was increased in EGFR-KO mice in the long-term study, which correlated with activation of transforming growth factor-β/fibrosis signaling pathways. Further, nuclear levels of some of the major MASLD regulating transcription factors (SREBP1, PPARγ, PPARα, and HNF4α) were altered in FFD-fed EGFR-KO mice. Transcriptomic analysis revealed significant alteration of lipid metabolism pathways in EGFR-KO mice with changes in several relevant genes, including downregulation of fatty-acid synthase and induction of lipolysis gene, <em>Pnpla2</em>, without impacting overall steatosis. Interestingly, EGFR downstream signaling mediators, including AKT, remain activated in EGFR-KO mice, which correlated with increased activity pattern of other receptor tyrosine kinases, including ErbB3/MET, in transcriptomic analysis. Lastly, Canertinib treatment in EGFR-KO mice, which inhibits all ErbB receptors, successfully reduced steatosis, suggesting the compensatory roles of other ErbB receptors in supporting MASLD without EGFR.</p></div><div><h3>Conclusions</h3><p>Hepatocyte-specific EGFR-KO did not impact steatosis, but enhanced fibrosis in the FFD model of MASLD. Gene networks associated with lipid metabolism were greatly altered in EGFR-KO, but phenotypic effects might be compensated by alternate signaling pathways.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001358/pdfft?md5=e6751e746ab547c91ca49e7232a91af4&pid=1-s2.0-S2352345X24001358-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141749769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantifying Forms and Functions of Enterohepatic Bile Acid Pools in Mice","authors":"","doi":"10.1016/j.jcmgh.2024.101392","DOIUrl":"10.1016/j.jcmgh.2024.101392","url":null,"abstract":"<div><h3>Backgrounds &amp; Aims</h3><div>Bile acids (BAs) are core gastrointestinal metabolites with dual functions in lipid absorption and cell signaling. BAs circulate between the liver and distal small intestine (<em>i.e.</em>, ileum), yet the dynamics through which complex BA pools are absorbed in the ileum and interact with host intestinal cells <em>in vivo</em> remain poorly understood. Because ileal absorption is rate-limiting in determining which BAs in the intestinal lumen gain access to host intestinal cells and receptors, and at what concentrations, we hypothesized that defining the rates and routes of ileal BA absorption <em>in vivo</em> would yield novel insights into the physiological forms and functions of mouse enterohepatic BA pools.</div></div><div><h3>Methods</h3><div>Using <em>ex vivo</em> mass spectrometry, we quantified 88 BA species and metabolites in the intestinal lumen and superior mesenteric vein of individual wild-type mice, and cage-mates lacking the ileal BA transporter, Asbt/<em>Slc10a2</em>.</div></div><div><h3>Results</h3><div>Using these data, we calculated that the pool of BAs circulating through ileal tissue (<em>i.e.</em>, the ileal BA pool) in fasting C57BL/6J female mice is ∼0.3 μmol/g. Asbt-mediated transport accounted for ∼80% of this pool and amplified size. Passive permeability explained the remaining ∼20% and generated diversity. Compared with wild-type mice, the ileal BA pool in Asbt-deficient mice was ∼5-fold smaller, enriched in secondary BA species and metabolites normally found in the colon, and elicited unique transcriptional responses on addition to <em>ex</em> <em>vivo</em>–cultured ileal explants.</div></div><div><h3>Conclusions</h3><div>This study defines quantitative traits of the mouse enterohepatic BA pool and reveals how aberrant BA metabolism can impinge directly on host intestinal physiology.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142047593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysophosphatidic Acid Signaling in the Gastrointestinal System","authors":"","doi":"10.1016/j.jcmgh.2024.101398","DOIUrl":"10.1016/j.jcmgh.2024.101398","url":null,"abstract":"<div><div>The intestinal epithelium undergoes continuous homeostatic renewal to conduct the digestion and absorption of nutrients. At the same time, the intestinal epithelial barrier separates the host from the intestinal lumen, preventing systemic infection from enteric pathogens. To maintain homeostasis and epithelial functionality, stem cells, which reside in the base of intestinal crypts, generate progenitor cells that ultimately differentiate to produce an array of secretory and absorptive cells. Intestinal regeneration is regulated by niche signaling pathways, specifically, Wnt, bone morphogenetic protein, Notch, and epidermal growth factor. In addition, growth factors and other peptides have emerged as potential modulators of intestinal repair and inflammation through their roles in cellular proliferation, differentiation, migration, and survival. Lysophosphatidic acid (LPA) is such a factor that modulates the proliferation, survival, and migration of epithelial cells while also regulating trafficking of immune cells, both of which are important for tissue homeostasis. Perturbation of LPA signaling, however, has been shown to promote cancer and inflammation. This review focuses on the recent advances in LPA-mediated signaling that contribute to physiological and pathophysiological regulation of the gastrointestinal system.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Structure-function Analysis of Hepatocyte Arginase 2 Reveals Mitochondrial Ureahydrolysis as a Determinant of Glucose Oxidation","authors":"Yiming Zhang ,&nbsp;Jiameng Sun ,&nbsp;Henry D. Wasserman ,&nbsp;Joshua A. Adams ,&nbsp;Cassandra B. Higgins ,&nbsp;Shannon C. Kelly ,&nbsp;Louise Lantier ,&nbsp;Brian J. DeBosch","doi":"10.1016/j.jcmgh.2024.01.016","DOIUrl":"10.1016/j.jcmgh.2024.01.016","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Restoring hepatic and peripheral insulin sensitivity is critical to prevent or reverse metabolic syndrome and type 2 diabetes. Glucose homeostasis comprises in part the complex regulation of hepatic glucose production and insulin-mediated glucose uptake and oxidation in peripheral tissues. We previously identified hepatocyte arginase 2 (Arg2) as an inducible ureahydrolase that improves glucose homeostasis and enhances glucose oxidation in multiple obese, insulin-resistant models. We therefore examined structure-function determinants through which hepatocyte Arg2 governs systemic insulin action and glucose oxidation.</p></div><div><h3>Methods</h3><p>To do this, we generated mice expressing wild-type murine Arg2, enzymatically inactive Arg2 (Arg2^H160F) and Arg2 lacking its putative mitochondrial targeting sequence (Arg2^Δ1-22). We expressed these hepatocyte-specific constructs in obese, diabetic (<em>db/db</em>) mice and performed genetic complementation analyses in hepatocyte-specific Arg2-deficent (Arg2^LKO) mice.</p></div><div><h3>Results</h3><p>We show that Arg2 attenuates hepatic steatosis, independent of mitochondrial localization or ureahydrolase activity, and that enzymatic arginase activity is dispensable for Arg2 to augment total body energy expenditure. In contrast, mitochondrial localization and ureahydrolase activity were required for Arg2-mediated reductions in fasting glucose and insulin resistance indices. Mechanistically, Arg2^Δ1-22 and Arg2^H160F failed to suppress glucose appearance during hyperinsulinemic-euglycemic clamping. Quantification of heavy-isotope-labeled glucose oxidation further revealed that mistargeting or ablating Arg2 enzymatic function abrogates Arg2-induced peripheral glucose oxidation.</p></div><div><h3>Conclusion</h3><p>We conclude that the metabolic effects of Arg2 extend beyond its enzymatic activity, yet hepatocyte mitochondrial ureahydrolysis drives hepatic and peripheral oxidative metabolism. The data define a structure-based mechanism mediating hepatocyte Arg2 function and nominate hepatocyte mitochondrial ureahydrolysis as a key determinant of glucose oxidative capacity in mammals.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000158/pdfft?md5=0fd591e61735c79bae9adb664cc7aec3&pid=1-s2.0-S2352345X24000158-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139555965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}