Pub Date : 2024-10-30DOI: 10.1016/j.ebiom.2024.105412
Yongtao Wang, Emeli Chatterjee, Guoping Li, Jiahong Xu, Junjie Xiao
Force-sensing biophysical cues in microenvironment, including extracellular matrix performances, stretch-mediated mechanics, shear stress and flow-induced hemodynamics, have a significant influence in regulating vascular morphogenesis and cardiac remodeling by mechanotransduction. Once cells perceive these extracellular mechanical stimuli, Piezo activation promotes calcium influx by forming integrin-adhesion-coupling receptors. This induces robust contractility of cytoskeleton structures to further transmit biomechanical alternations into nuclei by regulating Hippo-Yes associated protein (YAP) signaling pathway between cytoplasmic and nuclear translocation. Although biomechanical stimuli are widely studied in cardiovascular diseases, the expression of force-sensing proteins in response to cardiovascular mechanotransduction has not been systematically concluded. Therefore, this review will summarize the force-sensing Piezo, cytoskeleton and YAP proteins to mediate extracellular mechanics, and also give the prominent emphasis on intrinsic connection of these mechanical proteins and cardiovascular mechanotransduction. Extensive insights into cardiovascular mechanics may provide some new strategies for cardiovascular clinical therapy.
{"title":"Force-sensing protein expression in response to cardiovascular mechanotransduction.","authors":"Yongtao Wang, Emeli Chatterjee, Guoping Li, Jiahong Xu, Junjie Xiao","doi":"10.1016/j.ebiom.2024.105412","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105412","url":null,"abstract":"<p><p>Force-sensing biophysical cues in microenvironment, including extracellular matrix performances, stretch-mediated mechanics, shear stress and flow-induced hemodynamics, have a significant influence in regulating vascular morphogenesis and cardiac remodeling by mechanotransduction. Once cells perceive these extracellular mechanical stimuli, Piezo activation promotes calcium influx by forming integrin-adhesion-coupling receptors. This induces robust contractility of cytoskeleton structures to further transmit biomechanical alternations into nuclei by regulating Hippo-Yes associated protein (YAP) signaling pathway between cytoplasmic and nuclear translocation. Although biomechanical stimuli are widely studied in cardiovascular diseases, the expression of force-sensing proteins in response to cardiovascular mechanotransduction has not been systematically concluded. Therefore, this review will summarize the force-sensing Piezo, cytoskeleton and YAP proteins to mediate extracellular mechanics, and also give the prominent emphasis on intrinsic connection of these mechanical proteins and cardiovascular mechanotransduction. Extensive insights into cardiovascular mechanics may provide some new strategies for cardiovascular clinical therapy.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-30DOI: 10.1016/j.ebiom.2024.105426
Mikael Hakkola, Sofia Ainonen, Eveliina Ronkainen, Minna Honkila, Marika Paalanne, Tytti Pokka, Eero Kajantie, Niko Paalanne, Terhi Ruuska-Loewald
Background: Intrapartum antibiotics are used to prevent group B streptococcus disease in newborn infants. We hypothesised that intrapartum antibiotic exposure is associated with the occurrence of childhood infectious diseases because it influences the development of the gut microbiome.
Methods: The cohort for this population-based study comprised vaginally delivered children born in Northern Finland in 2007-2018. We used structured electronic medical records linked to comprehensive national registers. Primary outcome was the number of infectious disease episodes leading to an emergency room visit, outpatient hospital visit, or hospitalisation from birth until five years of age.
Findings: Analyses were performed on 9733 children (48.8% girls) exposed to intrapartum antibiotics and on 35,842 unexposed children (49.9% girls). Exposure to intrapartum antibiotics was associated with increased risk of any infectious disease episode at the ages 7-28 days (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.10-1.54) and 1-2 years (aIRR 1.10, 95% CI 1.02-1.18). The occurrence of urinary tract infections was associated with the exposure to intrapartum antibiotics whereas the occurrence of severe infections caused by pathogens susceptible to penicillin was reversely associated with the exposure to intrapartum antibiotics.
Interpretation: Maternal intrapartum antibiotics were associated with the occurrence of infectious diseases in the offspring. The observed associations appeared to depend on bacterial pathogens and their antimicrobial susceptibility to penicillin.
Funding: Pediatric Research Foundation, Alma och K.A. Snellman Foundation, Orion Research Foundation, Päivikki and Sakari Sohlberg Foundation, Finnish Medical Foundation, Academy of Finland, Finland.
背景:产前使用抗生素可预防新生儿B组链球菌疾病。我们假设,产前接触抗生素会影响肠道微生物组的发育,因此与儿童传染病的发生有关:这项人群研究的队列包括 2007-2018 年在芬兰北部阴道分娩的婴儿。我们使用了与国家综合登记册相链接的结构化电子病历。主要结果是儿童从出生到五岁期间因传染病导致急诊就诊、医院门诊就诊或住院的次数:对9733名产前接触过抗生素的儿童(48.8%为女童)和35842名未接触过抗生素的儿童(49.9%为女童)进行了分析。接触产前抗生素与 7-28 天(调整后发病率比 [aIRR] 1.30,95% CI 1.10-1.54)和 1-2 岁(调整后发病率比 1.10,95% CI 1.02-1.18)的感染性疾病发病风险增加有关。尿路感染的发生与产前抗生素的接触有关,而对青霉素敏感的病原体引起的严重感染的发生与产前抗生素的接触成反比:解释:母体产前使用抗生素与后代感染性疾病的发生有关。观察到的关联似乎取决于细菌病原体及其对青霉素的抗菌敏感性:芬兰儿科研究基金会、Alma och K.A. Snellman基金会、猎户座研究基金会、Päivikki和Sakari Sohlberg基金会、芬兰医学基金会、芬兰科学院。
{"title":"Intrapartum antibiotic exposure and infectious diseases in childhood - a population-based cohort study.","authors":"Mikael Hakkola, Sofia Ainonen, Eveliina Ronkainen, Minna Honkila, Marika Paalanne, Tytti Pokka, Eero Kajantie, Niko Paalanne, Terhi Ruuska-Loewald","doi":"10.1016/j.ebiom.2024.105426","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105426","url":null,"abstract":"<p><strong>Background: </strong>Intrapartum antibiotics are used to prevent group B streptococcus disease in newborn infants. We hypothesised that intrapartum antibiotic exposure is associated with the occurrence of childhood infectious diseases because it influences the development of the gut microbiome.</p><p><strong>Methods: </strong>The cohort for this population-based study comprised vaginally delivered children born in Northern Finland in 2007-2018. We used structured electronic medical records linked to comprehensive national registers. Primary outcome was the number of infectious disease episodes leading to an emergency room visit, outpatient hospital visit, or hospitalisation from birth until five years of age.</p><p><strong>Findings: </strong>Analyses were performed on 9733 children (48.8% girls) exposed to intrapartum antibiotics and on 35,842 unexposed children (49.9% girls). Exposure to intrapartum antibiotics was associated with increased risk of any infectious disease episode at the ages 7-28 days (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.10-1.54) and 1-2 years (aIRR 1.10, 95% CI 1.02-1.18). The occurrence of urinary tract infections was associated with the exposure to intrapartum antibiotics whereas the occurrence of severe infections caused by pathogens susceptible to penicillin was reversely associated with the exposure to intrapartum antibiotics.</p><p><strong>Interpretation: </strong>Maternal intrapartum antibiotics were associated with the occurrence of infectious diseases in the offspring. The observed associations appeared to depend on bacterial pathogens and their antimicrobial susceptibility to penicillin.</p><p><strong>Funding: </strong>Pediatric Research Foundation, Alma och K.A. Snellman Foundation, Orion Research Foundation, Päivikki and Sakari Sohlberg Foundation, Finnish Medical Foundation, Academy of Finland, Finland.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-30DOI: 10.1016/j.ebiom.2024.105416
Paul Yangho Park, Lauren Elizabeth Bleakley, Nadia Saraya, Reem Al-Jawahiri, Josefine Eck, Marc Anthony Aloi, Holly Melland, Kate Baker, Sarah Louise Gordon
Background: Pathogenic missense variants in the essential synaptic vesicle protein synaptotagmin-1 (SYT1) cause a neurodevelopmental disorder characterised by motor delay and intellectual disability, hyperkinetic movement disorder, episodic agitation, and visual impairments. SYT1 is the presynaptic calcium sensor that triggers synchronous neurotransmitter release. We have previously shown that pathogenic variants around the calcium-sensing region of the critical C2B domain decrease synaptic vesicle exocytosis in neurons.
Methods: Here, we have used cultured hippocampal neurons transfected with SYT1-pHluorin to examine how variants within the C2A and C2B domain of SYT1 impact evoked exocytosis.
Findings: We show that recently identified variants within the facilitatory C2A domain of the protein (L159R, T196K, E209K, E219Q), as well as additional variants in the C2B domain (M303V, S309P, Y365C, G369D), share an underlying pathogenic mechanism, causing a graded and variant-dependent dominant-negative impairment in exocytosis. We establish that the extent of evoked exocytosis observed in vitro in the presence of SYT1 variants correlates with neurodevelopmental impacts of this disorder. Specifically, the severity of motor and communication impairments exhibited by individuals harbouring these variants correlates with multiple measures of exocytic efficiency.
Interpretation: Together, this suggests that there is a genotype-function-phenotype relationship in SYT1-associated neurodevelopmental disorder, centring impaired evoked neurotransmitter release as a common pathogenic driver. Moreover, this points toward a direct link between control of neurotransmitter release and development of adaptive functions, providing a tractable target for therapeutic amelioration.
Funding: Australian National Health and Medical Research Council, UK Medical Research Council, Great Ormond Street Hospital Children's Charity, University of Melbourne.
{"title":"Correlation between evoked neurotransmitter release and adaptive functions in SYT1-associated neurodevelopmental disorder.","authors":"Paul Yangho Park, Lauren Elizabeth Bleakley, Nadia Saraya, Reem Al-Jawahiri, Josefine Eck, Marc Anthony Aloi, Holly Melland, Kate Baker, Sarah Louise Gordon","doi":"10.1016/j.ebiom.2024.105416","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105416","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic missense variants in the essential synaptic vesicle protein synaptotagmin-1 (SYT1) cause a neurodevelopmental disorder characterised by motor delay and intellectual disability, hyperkinetic movement disorder, episodic agitation, and visual impairments. SYT1 is the presynaptic calcium sensor that triggers synchronous neurotransmitter release. We have previously shown that pathogenic variants around the calcium-sensing region of the critical C2B domain decrease synaptic vesicle exocytosis in neurons.</p><p><strong>Methods: </strong>Here, we have used cultured hippocampal neurons transfected with SYT1-pHluorin to examine how variants within the C2A and C2B domain of SYT1 impact evoked exocytosis.</p><p><strong>Findings: </strong>We show that recently identified variants within the facilitatory C2A domain of the protein (L159R, T196K, E209K, E219Q), as well as additional variants in the C2B domain (M303V, S309P, Y365C, G369D), share an underlying pathogenic mechanism, causing a graded and variant-dependent dominant-negative impairment in exocytosis. We establish that the extent of evoked exocytosis observed in vitro in the presence of SYT1 variants correlates with neurodevelopmental impacts of this disorder. Specifically, the severity of motor and communication impairments exhibited by individuals harbouring these variants correlates with multiple measures of exocytic efficiency.</p><p><strong>Interpretation: </strong>Together, this suggests that there is a genotype-function-phenotype relationship in SYT1-associated neurodevelopmental disorder, centring impaired evoked neurotransmitter release as a common pathogenic driver. Moreover, this points toward a direct link between control of neurotransmitter release and development of adaptive functions, providing a tractable target for therapeutic amelioration.</p><p><strong>Funding: </strong>Australian National Health and Medical Research Council, UK Medical Research Council, Great Ormond Street Hospital Children's Charity, University of Melbourne.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1016/j.ebiom.2024.105421
Md Nazmul Hossain, Yao Gao, Xinrui Li, Liang Zhao, Xiangdong Liu, Jeanene Marie de Avila, Mei-Jun Zhu, Min Du
Background: Over 40% of pregnant women in the USA are obese which negatively affects fetal development and offspring health. Maternal obesity (MO) leads to fibrotic infiltration in multiple tissues and organs of offspring during their adulthood although the origin and mechanisms are unclear.
Methods: C57BL/6J female mice were fed a control and high-fat diet to mimic MO condition. Embryonic somatic tissues were obtained at E9.5, E11.5, and E13.5 (equivalent to 6 weeks of human pregnancy) from control (CON) and MO mice for single-cell RNA-sequencing (scRNA-seq). To explore the role of AMP-activated protein kinase (AMPK), AMPK was activated by metformin and A769662, and knocked out in embryonic mesenchymal cells (EMC) using AMPKα1 floxed mice.
Findings: Using unsupervised clustering, we identified three major cell populations with fibrogenic capacity. Compared to CON, the population of fibrogenic cells increased dramatically (by ∼125%) due to MO, supporting an embryonic origin of fibrosis in the offspring. MO induced inflammatory response and elevated expression of transforming growth factor β (TGFβ) signalling and fibrogenic genes in embryos. MO inhibited AMPK and its activation by metformin and A769662 inhibited TGFβ signalling and fibrogenesis.
Interpretation: MO profoundly enhances embryonic fibrogenesis, explaining the origin of fibrosis in the offspring of mothers living with obesity. Our data underscore the importance of early intervention, before 5-6 weeks of pregnancy, in improving embryonic development, and AMPK is an amiable target for suppressing excessive fibrogenesis in MO embryos to assist increasing populations of obese mothers having healthy children.
Funding: This work was funded by National Institutes of Health Grant R01HD067449.
{"title":"Single-cell RNA transcriptomics in mice reveals embryonic origin of fibrosis due to maternal obesity.","authors":"Md Nazmul Hossain, Yao Gao, Xinrui Li, Liang Zhao, Xiangdong Liu, Jeanene Marie de Avila, Mei-Jun Zhu, Min Du","doi":"10.1016/j.ebiom.2024.105421","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105421","url":null,"abstract":"<p><strong>Background: </strong>Over 40% of pregnant women in the USA are obese which negatively affects fetal development and offspring health. Maternal obesity (MO) leads to fibrotic infiltration in multiple tissues and organs of offspring during their adulthood although the origin and mechanisms are unclear.</p><p><strong>Methods: </strong>C57BL/6J female mice were fed a control and high-fat diet to mimic MO condition. Embryonic somatic tissues were obtained at E9.5, E11.5, and E13.5 (equivalent to 6 weeks of human pregnancy) from control (CON) and MO mice for single-cell RNA-sequencing (scRNA-seq). To explore the role of AMP-activated protein kinase (AMPK), AMPK was activated by metformin and A769662, and knocked out in embryonic mesenchymal cells (EMC) using AMPKα1 floxed mice.</p><p><strong>Findings: </strong>Using unsupervised clustering, we identified three major cell populations with fibrogenic capacity. Compared to CON, the population of fibrogenic cells increased dramatically (by ∼125%) due to MO, supporting an embryonic origin of fibrosis in the offspring. MO induced inflammatory response and elevated expression of transforming growth factor β (TGFβ) signalling and fibrogenic genes in embryos. MO inhibited AMPK and its activation by metformin and A769662 inhibited TGFβ signalling and fibrogenesis.</p><p><strong>Interpretation: </strong>MO profoundly enhances embryonic fibrogenesis, explaining the origin of fibrosis in the offspring of mothers living with obesity. Our data underscore the importance of early intervention, before 5-6 weeks of pregnancy, in improving embryonic development, and AMPK is an amiable target for suppressing excessive fibrogenesis in MO embryos to assist increasing populations of obese mothers having healthy children.</p><p><strong>Funding: </strong>This work was funded by National Institutes of Health Grant R01HD067449.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1016/j.ebiom.2024.105436
Li Song, Chunyan Zhu, Qing Shi, Yuhan Xia, Xiayi Liang, Wen Qin, Tao Ye, Biwei Yang, Xin Cao, Jinglin Xia, Kun Zhang
Background: Current embolic agents in transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) encounter instability and easy leakage, discounting TACE efficacy with residual HCC. Moreover, clinical TACE aggravates hypoxia and pro-metastatic microenvironments, rendering patients with HCC poor prognosis.
Methods: Herein, we developed Zein-based embolic agents that harness water-insoluble but ethanol-soluble Zein to encompass doxorubicin (DOX)-loaded mesoporous hollow MnO2 (HMnO2). The conditions and capacity of HMnO2 to generate reactive oxygen species (ROS) were assayed. Mechanical examinations of Zein-HMnO2@DOX were performed to evaluate its potential as the embolic agent. In vitro experiments were carried out to evaluate the effect of Zein-HMnO2@DOX on HCC. The subcutaneous HCC mouse model and rabbit VX2 HCC model were established to investigate its anti-tumor and anti-metastasis efficacy and explore its potential anti-tumor mechanism.
Findings: The high adhesion and crosslinking of Zein with HMnO2@DOX impart Zein-HMnO2@DOX with strong mechanical strength to resist deformation and wash-off. Zein gelation and HMnO2 decomposition in response to water and acidic tumor microenvironment, respectively, enable continuous DOX release and Fenton-like reaction for reactive oxygen species (ROS) production and O2 release to execute ROS-enhanced TACE. Consequently, Zein-based embolic agents outperform clinically-used lipiodol to significantly inhibit orthotopic HCC growth. More significantly, O2 release down-regulates hypoxia inducible factor (HIF-1α), vascular endothelial growth factor (VEGF) and glucose transporter protein 1 (GLUT1), which thereby re-programmes TACE-aggravated hypoxic and pro-metastatic microenvironments to repress HCC metastasis towards lung. Mechanistic explorations uncover that such Zein-based TACE agents disrupt oxidative stress, angiogenesis and glycometabolism pathways to inhibit HCC progression.
Interpretation: This innovative work not only provides a new TACE agent for HCC, but also establishes a new strategy to ameliorate TACE-aggravated hypoxia and metastasis motivation against clinically-common HCC metastasis after TACE operation.
Funding: Excellent Young Science Fund for National Natural Science Foundation of China (82022033); National Natural Science Foundation of China (Grant No. 82373086, 82102761); Major scientific and technological innovation project of Wenzhou Science and Technology Bureau (Grant No. ZY2021009); Shanghai Young Top-Notch Talent.
{"title":"Gelation embolism agents suppress clinical TACE-incited pro-metastatic microenvironment against hepatocellular carcinoma progression.","authors":"Li Song, Chunyan Zhu, Qing Shi, Yuhan Xia, Xiayi Liang, Wen Qin, Tao Ye, Biwei Yang, Xin Cao, Jinglin Xia, Kun Zhang","doi":"10.1016/j.ebiom.2024.105436","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105436","url":null,"abstract":"<p><strong>Background: </strong>Current embolic agents in transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) encounter instability and easy leakage, discounting TACE efficacy with residual HCC. Moreover, clinical TACE aggravates hypoxia and pro-metastatic microenvironments, rendering patients with HCC poor prognosis.</p><p><strong>Methods: </strong>Herein, we developed Zein-based embolic agents that harness water-insoluble but ethanol-soluble Zein to encompass doxorubicin (DOX)-loaded mesoporous hollow MnO<sub>2</sub> (HMnO<sub>2</sub>). The conditions and capacity of HMnO<sub>2</sub> to generate reactive oxygen species (ROS) were assayed. Mechanical examinations of Zein-HMnO<sub>2</sub>@DOX were performed to evaluate its potential as the embolic agent. In vitro experiments were carried out to evaluate the effect of Zein-HMnO<sub>2</sub>@DOX on HCC. The subcutaneous HCC mouse model and rabbit VX2 HCC model were established to investigate its anti-tumor and anti-metastasis efficacy and explore its potential anti-tumor mechanism.</p><p><strong>Findings: </strong>The high adhesion and crosslinking of Zein with HMnO<sub>2</sub>@DOX impart Zein-HMnO<sub>2</sub>@DOX with strong mechanical strength to resist deformation and wash-off. Zein gelation and HMnO<sub>2</sub> decomposition in response to water and acidic tumor microenvironment, respectively, enable continuous DOX release and Fenton-like reaction for reactive oxygen species (ROS) production and O<sub>2</sub> release to execute ROS-enhanced TACE. Consequently, Zein-based embolic agents outperform clinically-used lipiodol to significantly inhibit orthotopic HCC growth. More significantly, O<sub>2</sub> release down-regulates hypoxia inducible factor (HIF-1α), vascular endothelial growth factor (VEGF) and glucose transporter protein 1 (GLUT1), which thereby re-programmes TACE-aggravated hypoxic and pro-metastatic microenvironments to repress HCC metastasis towards lung. Mechanistic explorations uncover that such Zein-based TACE agents disrupt oxidative stress, angiogenesis and glycometabolism pathways to inhibit HCC progression.</p><p><strong>Interpretation: </strong>This innovative work not only provides a new TACE agent for HCC, but also establishes a new strategy to ameliorate TACE-aggravated hypoxia and metastasis motivation against clinically-common HCC metastasis after TACE operation.</p><p><strong>Funding: </strong>Excellent Young Science Fund for National Natural Science Foundation of China (82022033); National Natural Science Foundation of China (Grant No. 82373086, 82102761); Major scientific and technological innovation project of Wenzhou Science and Technology Bureau (Grant No. ZY2021009); Shanghai Young Top-Notch Talent.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1016/j.ebiom.2024.105384
Melissa Nevarez-Brewster, Catherine H Demers, LillyBelle K Deer, Özlü Aran, Robert J Gallop, Mercedes Hoeflich Haase, Khalid Al-Ali, Maria M Bagonis, John H Gilmore, M Camille Hoffman, Martin A Styner, Benjamin L Hankin, Elysia Poggi Davis
Background: Poor prenatal maternal sleep is a pervasive, yet modifiable, health concern affecting maternal and foetal wellbeing. Experimental rodent studies demonstrate that prenatal maternal sleep deprivation affects offspring brain development and leads to adverse outcomes, including increased anxiety-like behaviour. We examined the relation between prenatal maternal sleep quality and neonatal white matter development and subsequent infant negative emotionality.
Methods: Participants included 116 mother-infant (53% female) dyads. Prenatal sleep quality was prospectively assessed three times during gestation (16, 29, and 35 gestational weeks) using the Pittsburgh Sleep Quality Index. Neonatal white matter, as indexed by fractional anisotropy (FA), was assessed via diffusion weighted magnetic resonance imaging. Negative emotionality was measured via behavioural observation and maternal report when the infant was 6-months of age.
Findings: More prenatal sleep problems across pregnancy were associated with higher neonatal FA in the uncinate fasciculus (left: b = 0.20, p = .004; right: b = 0.15, p = .027). Higher neonatal uncinate FA was linked to infant negative emotionality, and uncinate FA partially mediated the association between prenatal maternal sleep and behavioural observation of infant negative emotionality.
Interpretation: Findings highlight prenatal sleep as an environmental signal that affects the developing neonatal brain and later infant negative emotionality.
Funding: National Institutes of Health (R01MH109662, R01HL155744, P50HD103573, K12AR084226, F32 Training fellowships MH125572, HL165844, MH106440, and diversity supplement R01HL155744-01S1).
{"title":"Association between prenatal maternal sleep quality, neonatal uncinate fasciculus white matter, and infant negative emotionality.","authors":"Melissa Nevarez-Brewster, Catherine H Demers, LillyBelle K Deer, Özlü Aran, Robert J Gallop, Mercedes Hoeflich Haase, Khalid Al-Ali, Maria M Bagonis, John H Gilmore, M Camille Hoffman, Martin A Styner, Benjamin L Hankin, Elysia Poggi Davis","doi":"10.1016/j.ebiom.2024.105384","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105384","url":null,"abstract":"<p><strong>Background: </strong>Poor prenatal maternal sleep is a pervasive, yet modifiable, health concern affecting maternal and foetal wellbeing. Experimental rodent studies demonstrate that prenatal maternal sleep deprivation affects offspring brain development and leads to adverse outcomes, including increased anxiety-like behaviour. We examined the relation between prenatal maternal sleep quality and neonatal white matter development and subsequent infant negative emotionality.</p><p><strong>Methods: </strong>Participants included 116 mother-infant (53% female) dyads. Prenatal sleep quality was prospectively assessed three times during gestation (16, 29, and 35 gestational weeks) using the Pittsburgh Sleep Quality Index. Neonatal white matter, as indexed by fractional anisotropy (FA), was assessed via diffusion weighted magnetic resonance imaging. Negative emotionality was measured via behavioural observation and maternal report when the infant was 6-months of age.</p><p><strong>Findings: </strong>More prenatal sleep problems across pregnancy were associated with higher neonatal FA in the uncinate fasciculus (left: b = 0.20, p = .004; right: b = 0.15, p = .027). Higher neonatal uncinate FA was linked to infant negative emotionality, and uncinate FA partially mediated the association between prenatal maternal sleep and behavioural observation of infant negative emotionality.</p><p><strong>Interpretation: </strong>Findings highlight prenatal sleep as an environmental signal that affects the developing neonatal brain and later infant negative emotionality.</p><p><strong>Funding: </strong>National Institutes of Health (R01MH109662, R01HL155744, P50HD103573, K12AR084226, F32 Training fellowships MH125572, HL165844, MH106440, and diversity supplement R01HL155744-01S1).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1016/j.ebiom.2024.105420
Yi-Rao Zhou, Jun-Jie Dang, Qi-Chao Yang, Zhi-Jun Sun
Pyroptosis, a type of programmed cell death mediated by gasdermin family proteins, releases a large amount of immune stimulatory substances, which further contribute to inflammation and elicit an adaptive immune response against tumours and pathogens. And it occurs through multiple pathways that involve the activation of specific caspases and the cleavage of gasdermins. Post-translational modifications (PTMs) could influence the chemical properties of the modified residues and neighbouring regions, ultimately affecting the activity, stability, and functions of proteins to regulate pyroptosis. Many studies have been conducted to explore the influence of PTMs on the regulation of pyroptosis. In this review, we provide a comprehensive summary of different types of PTMs that influence pyroptosis, along with their corresponding modifying enzymes. Moreover, it elaborates on the specific contributions of different PTMs to pyroptosis and delves into how the regulation of these modifications can be leveraged for therapeutic interventions in cancer and inflammatory diseases.
{"title":"The regulation of pyroptosis by post-translational modifications: molecular mechanisms and therapeutic targets.","authors":"Yi-Rao Zhou, Jun-Jie Dang, Qi-Chao Yang, Zhi-Jun Sun","doi":"10.1016/j.ebiom.2024.105420","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105420","url":null,"abstract":"<p><p>Pyroptosis, a type of programmed cell death mediated by gasdermin family proteins, releases a large amount of immune stimulatory substances, which further contribute to inflammation and elicit an adaptive immune response against tumours and pathogens. And it occurs through multiple pathways that involve the activation of specific caspases and the cleavage of gasdermins. Post-translational modifications (PTMs) could influence the chemical properties of the modified residues and neighbouring regions, ultimately affecting the activity, stability, and functions of proteins to regulate pyroptosis. Many studies have been conducted to explore the influence of PTMs on the regulation of pyroptosis. In this review, we provide a comprehensive summary of different types of PTMs that influence pyroptosis, along with their corresponding modifying enzymes. Moreover, it elaborates on the specific contributions of different PTMs to pyroptosis and delves into how the regulation of these modifications can be leveraged for therapeutic interventions in cancer and inflammatory diseases.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1016/j.ebiom.2024.105404
Karen L Oliver, Ingrid E Scheffer, Colin A Ellis, Bronwyn E Grinton, Samuel F Berkovic, Melanie Bahlo
Background: Phenotypic variability within families with epilepsy is often observed, even when relatives share the same monogenic cause. We aimed to investigate whether common polygenic risk for epilepsy could explain the penetrance and phenotypic expression of rare pathogenic variants in familial epilepsies.
Methods: We studied 58 clinically heterogeneous families with genetic epilepsy with febrile seizures plus (GEFS+). Relatives were coded as either unaffected or affected with epilepsy, and graded according to phenotype severity: no seizures, febrile seizures (FS) only, febrile seizures plus (FS+), generalised/focal epilepsy, or developmental and epileptic encephalopathy (DEE). Epilepsy polygenic risk scores (PRSs) were tested for association with epilepsy phenotype. Within families, the mean PRS difference was compared between pairs concordant versus discordant for phenotype severity. Statistical analyses were performed using mixed-effect regression models.
Findings: 304 individuals segregating a known, or presumed, rare variant of large effect, were studied. Within families, higher epilepsy polygenic risk was associated with an epilepsy diagnosis (OR = 1.39, 95% CI 1.08, 1.80, padj = 0.040). Relatives with a more severe phenotype had a mean pairwise PRS difference of +0.19 higher than relatives with a milder phenotype (padj = 0.010). The difference increased with greater phenotype discordance between relatives. As the cohort included two rare variants with >30 relatives each, variant-specific genotype-phenotype associations could also be analysed. Whilst the epilepsy PRS effect was strong for relatives segregating the GABRG2 p.Arg82Gln pathogenic variant (padj = 0.0010), the effect was not significant for SCN1B p.Cys121Trp.
Interpretation: We provide support for genetic background modifying the penetrance and phenotypic expression of rare variants associated with 'monogenic' epilepsies. In GEFS+ families, relatives with higher epilepsy PRSs were more likely to show penetrance (epilepsy diagnosis) and a more severe phenotype. Variant-specific analyses suggest that some rare variants may be more susceptible to PRS modification, carrying important genetic counselling and disease prognostication implications for patients.
Funding: National Health and Medical Research Council of Australia, Medical Research Future Fund of Australia.
{"title":"Investigating the effect of polygenic background on epilepsy phenotype in 'monogenic' families.","authors":"Karen L Oliver, Ingrid E Scheffer, Colin A Ellis, Bronwyn E Grinton, Samuel F Berkovic, Melanie Bahlo","doi":"10.1016/j.ebiom.2024.105404","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105404","url":null,"abstract":"<p><strong>Background: </strong>Phenotypic variability within families with epilepsy is often observed, even when relatives share the same monogenic cause. We aimed to investigate whether common polygenic risk for epilepsy could explain the penetrance and phenotypic expression of rare pathogenic variants in familial epilepsies.</p><p><strong>Methods: </strong>We studied 58 clinically heterogeneous families with genetic epilepsy with febrile seizures plus (GEFS+). Relatives were coded as either unaffected or affected with epilepsy, and graded according to phenotype severity: no seizures, febrile seizures (FS) only, febrile seizures plus (FS+), generalised/focal epilepsy, or developmental and epileptic encephalopathy (DEE). Epilepsy polygenic risk scores (PRSs) were tested for association with epilepsy phenotype. Within families, the mean PRS difference was compared between pairs concordant versus discordant for phenotype severity. Statistical analyses were performed using mixed-effect regression models.</p><p><strong>Findings: </strong>304 individuals segregating a known, or presumed, rare variant of large effect, were studied. Within families, higher epilepsy polygenic risk was associated with an epilepsy diagnosis (OR = 1.39, 95% CI 1.08, 1.80, p<sub>adj</sub> = 0.040). Relatives with a more severe phenotype had a mean pairwise PRS difference of +0.19 higher than relatives with a milder phenotype (p<sub>adj</sub> = 0.010). The difference increased with greater phenotype discordance between relatives. As the cohort included two rare variants with >30 relatives each, variant-specific genotype-phenotype associations could also be analysed. Whilst the epilepsy PRS effect was strong for relatives segregating the GABRG2 p.Arg82Gln pathogenic variant (p<sub>adj</sub> = 0.0010), the effect was not significant for SCN1B p.Cys121Trp.</p><p><strong>Interpretation: </strong>We provide support for genetic background modifying the penetrance and phenotypic expression of rare variants associated with 'monogenic' epilepsies. In GEFS+ families, relatives with higher epilepsy PRSs were more likely to show penetrance (epilepsy diagnosis) and a more severe phenotype. Variant-specific analyses suggest that some rare variants may be more susceptible to PRS modification, carrying important genetic counselling and disease prognostication implications for patients.</p><p><strong>Funding: </strong>National Health and Medical Research Council of Australia, Medical Research Future Fund of Australia.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.ebiom.2024.105418
Mégane Willems, Malik Hamaidia, Alexis Fontaine, Mélanie Grégoire, Louise Halkin, Lea Vilanova Mañá, Roxane Terres, Majeed Jamakhani, Sophie Deshayes, Yves Brostaux, Vincent Heinen, Renaud Louis, Bernard Duysinx, Didier Jean, Eric Wasielewski, Arnaud Scherpereel, Christophe Blanquart, Luc Willems
Background: In mesothelioma (MPM), clinical evidence indicates that the absolute eosinophil count negatively correlates with overall survival and response to standard chemotherapy. Since eosinophils poorly infiltrate MPM tumours, we hypothesised that endocrine rather than paracrine pathways mediate the therapeutic response. We thus studied the effect of eosinophil-associated factors on response to chemotherapy in mesothelioma.
Methods: The culture supernatant conditioned by primary human eosinophils was added to mesothelioma cells in presence of the standard chemotherapeutic regimen. The effectiveness of an anti-eosinophil treatment was evaluated in a preclinical model of C57BL/6 mice transplanted with mesothelioma tumour cells.
Findings: Supernatant of eosinophils differentiated from EOL1 cells or directly isolated from peripheral blood inhibited apoptosis induced by cisplatin and pemetrexed in 2D cultures and in spheroids. Transcriptomic analysis indicated that the anti-apoptotic effect mediated by eosinophils involved molecular interactions with the Charcot-Leyden Crystal protein or Galectin-10 (CLC-P/Gal10). The functional relevance of CLC-P/Gal10 was demonstrated by antibody-mediated depletion. Recombinant human CLC-P/Gal10 mimicked the anti-apoptotic activity of eosinophil-derived supernatants. In the mouse model, eosinophilia did not significantly affect tumour growth but altered the response to chemotherapy. Finally, pretreatment of eosinophilia with the anti-Siglec-F antibody before chemotherapy restored the effectiveness of the treatment.
Interpretation: This study provides a mechanistic rationale to clinical evidence correlating the poor outcome of patients with mesothelioma and with eosinophil-derived CLC-P/Gal10, opening new prospects for intervention in this fatal solid tumour.
Funding: Belgian Foundation against Cancer, Fonds National de la Recherche Scientifique (FNRS), Télévie, Foundation Léon Fredericq, ULiège.
{"title":"The impact of Charcot-Leyden Crystal protein on mesothelioma chemotherapy: targeting eosinophils for enhanced chemosensitivity.","authors":"Mégane Willems, Malik Hamaidia, Alexis Fontaine, Mélanie Grégoire, Louise Halkin, Lea Vilanova Mañá, Roxane Terres, Majeed Jamakhani, Sophie Deshayes, Yves Brostaux, Vincent Heinen, Renaud Louis, Bernard Duysinx, Didier Jean, Eric Wasielewski, Arnaud Scherpereel, Christophe Blanquart, Luc Willems","doi":"10.1016/j.ebiom.2024.105418","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105418","url":null,"abstract":"<p><strong>Background: </strong>In mesothelioma (MPM), clinical evidence indicates that the absolute eosinophil count negatively correlates with overall survival and response to standard chemotherapy. Since eosinophils poorly infiltrate MPM tumours, we hypothesised that endocrine rather than paracrine pathways mediate the therapeutic response. We thus studied the effect of eosinophil-associated factors on response to chemotherapy in mesothelioma.</p><p><strong>Methods: </strong>The culture supernatant conditioned by primary human eosinophils was added to mesothelioma cells in presence of the standard chemotherapeutic regimen. The effectiveness of an anti-eosinophil treatment was evaluated in a preclinical model of C57BL/6 mice transplanted with mesothelioma tumour cells.</p><p><strong>Findings: </strong>Supernatant of eosinophils differentiated from EOL1 cells or directly isolated from peripheral blood inhibited apoptosis induced by cisplatin and pemetrexed in 2D cultures and in spheroids. Transcriptomic analysis indicated that the anti-apoptotic effect mediated by eosinophils involved molecular interactions with the Charcot-Leyden Crystal protein or Galectin-10 (CLC-P/Gal10). The functional relevance of CLC-P/Gal10 was demonstrated by antibody-mediated depletion. Recombinant human CLC-P/Gal10 mimicked the anti-apoptotic activity of eosinophil-derived supernatants. In the mouse model, eosinophilia did not significantly affect tumour growth but altered the response to chemotherapy. Finally, pretreatment of eosinophilia with the anti-Siglec-F antibody before chemotherapy restored the effectiveness of the treatment.</p><p><strong>Interpretation: </strong>This study provides a mechanistic rationale to clinical evidence correlating the poor outcome of patients with mesothelioma and with eosinophil-derived CLC-P/Gal10, opening new prospects for intervention in this fatal solid tumour.</p><p><strong>Funding: </strong>Belgian Foundation against Cancer, Fonds National de la Recherche Scientifique (FNRS), Télévie, Foundation Léon Fredericq, ULiège.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}