Pub Date : 2024-09-19DOI: 10.1101/2024.09.11.612567
Micha Keller, Volker Perlitz, Holger Pelz, Stefan Borik, Ines Repik, Armin Geilgens, Birol Cotuk, Gero Müller, Klaus Mathiak, Johannes Mayer
Significant autonomic nervous system responses to a specific osteopathic intervention, the cranial vault hold (CVH), have recently been demonstrated in forehead skin blood volume changes, heart rate, and respiration frequencies. The specificity of the CVH-intervention-related autonomic responses yet requires differentiation. Thus, we compared autonomic responses to CVH with responses to compression of the fourth ventricle (CV4) and to two corresponding SHAM conditions. Analysis of frequencies and amplitudes for changes in skin blood volume and respiration in low (LF; 0.05 - 0.12 Hz), intermediate (IM; 0.12 - 0.18 Hz), and high (HF; 0.18 - 0.4 Hz) frequency bands, and metrics of heartrate variability revealed significant decreases in LF range (from 0.12 to 0.10 Hz), increased LF and decreased IM durations, and increased skin blood volume amplitudes in response to CVH, but no significant skin blood volume responses to any of the control interventions. Ratio changes for respiration and skin blood volume frequencies approximately at 3:1 during CVH, remained unchanged in all other interventions. Heart rate decreased across conditions, indicating an increase in parasympathetic tone. This was also indicated by a significant increase in root mean of squared successive difference following CV4. We incurred that rhythmic response patterns in the LF and IM bands only appeared in CVH. This suggests specific physiological responses to CVH warranting further investigation by studying e.g., responses to CVH in physical or mental health disorders with autonomic involvement.
{"title":"On the specificity of manual triggers of autonomic nervous system responses using osteopathic cranial manipulative medicine","authors":"Micha Keller, Volker Perlitz, Holger Pelz, Stefan Borik, Ines Repik, Armin Geilgens, Birol Cotuk, Gero Müller, Klaus Mathiak, Johannes Mayer","doi":"10.1101/2024.09.11.612567","DOIUrl":"https://doi.org/10.1101/2024.09.11.612567","url":null,"abstract":"Significant autonomic nervous system responses to a specific osteopathic intervention, the cranial vault hold (CVH), have recently been demonstrated in forehead skin blood volume changes, heart rate, and respiration frequencies. The specificity of the CVH-intervention-related autonomic responses yet requires differentiation. Thus, we compared autonomic responses to CVH with responses to compression of the fourth ventricle (CV4) and to two corresponding SHAM conditions. Analysis of frequencies and amplitudes for changes in skin blood volume and respiration in low (LF; 0.05 - 0.12 Hz), intermediate (IM; 0.12 - 0.18 Hz), and high (HF; 0.18 - 0.4 Hz) frequency bands, and metrics of heartrate variability revealed significant decreases in LF range (from 0.12 to 0.10 Hz), increased LF and decreased IM durations, and increased skin blood volume amplitudes in response to CVH, but no significant skin blood volume responses to any of the control interventions. Ratio changes for respiration and skin blood volume frequencies approximately at 3:1 during CVH, remained unchanged in all other interventions. Heart rate decreased across conditions, indicating an increase in parasympathetic tone. This was also indicated by a significant increase in root mean of squared successive difference following CV4. We incurred that rhythmic response patterns in the LF and IM bands only appeared in CVH. This suggests specific physiological responses to CVH warranting further investigation by studying e.g., responses to CVH in physical or mental health disorders with autonomic involvement.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"208 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.1101/2024.09.17.613543
John Paul Kennelly, Xu Xiao, Yajing Gao, Sumin Kim, Soon-Gook Hong, Miranda Villanueva, Alessandra Ferrari, Lauri Vanharanta, Alexander Nguyen, Rohith T. Nagari, Nikolas R. Burton, Marcus J. Tol, Andrew P. Becker, Min Jae Lee, Elina Ikonen, Keriann Backus, Julia J Mack, Peter Tontonoz
Hypercholesterolemia has long been implicated in endothelial cell (EC) dysfunction, but the mechanisms by which excess cholesterol causes vascular pathology are incompletely understood. Here we used a cholesterol-mimetic probe to map cholesterol-protein interactions in primary human ECs and discovered that cholesterol binds to and stabilizes the adhesion molecule VCAM-1. We show that accessible plasma membrane (PM) cholesterol in ECs is acutely responsive to inflammatory stimuli and that the nonvesicular cholesterol transporter Aster-A regulates VCAM-1 stability in activated ECs by controlling the size of this pool. Deletion of Aster-A in ECs increases VCAM-1 protein, promotes immune cell recruitment to vessels, and impairs pulmonary immune homeostasis. Conversely, depleting cholesterol from the endothelium in vivo dampens VCAM-1 induction in response to inflammatory stimuli. These findings identify cholesterol binding to VCAM-1 as a key step during EC activation and provide a biochemical explanation for the ability of excess membrane cholesterol to promote immune cell recruitment to the endothelium.
{"title":"Cholesterol binding to VCAM-1 promotes vascular inflammation","authors":"John Paul Kennelly, Xu Xiao, Yajing Gao, Sumin Kim, Soon-Gook Hong, Miranda Villanueva, Alessandra Ferrari, Lauri Vanharanta, Alexander Nguyen, Rohith T. Nagari, Nikolas R. Burton, Marcus J. Tol, Andrew P. Becker, Min Jae Lee, Elina Ikonen, Keriann Backus, Julia J Mack, Peter Tontonoz","doi":"10.1101/2024.09.17.613543","DOIUrl":"https://doi.org/10.1101/2024.09.17.613543","url":null,"abstract":"Hypercholesterolemia has long been implicated in endothelial cell (EC) dysfunction, but the mechanisms by which excess cholesterol causes vascular pathology are incompletely understood. Here we used a cholesterol-mimetic probe to map cholesterol-protein interactions in primary human ECs and discovered that cholesterol binds to and stabilizes the adhesion molecule VCAM-1. We show that accessible plasma membrane (PM) cholesterol in ECs is acutely responsive to inflammatory stimuli and that the nonvesicular cholesterol transporter Aster-A regulates VCAM-1 stability in activated ECs by controlling the size of this pool. Deletion of Aster-A in ECs increases VCAM-1 protein, promotes immune cell recruitment to vessels, and impairs pulmonary immune homeostasis. Conversely, depleting cholesterol from the endothelium in vivo dampens VCAM-1 induction in response to inflammatory stimuli. These findings identify cholesterol binding to VCAM-1 as a key step during EC activation and provide a biochemical explanation for the ability of excess membrane cholesterol to promote immune cell recruitment to the endothelium.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1101/2024.09.12.612758
Hong Wang, Pablo A Ortiz, Cesar A Romero
Background: Renal autoregulatory mechanisms modulate renal blood flow. Connecting tubule glomerular feedback (CNTGF) is a vasodilator mechanism in the connecting tubule (CNT), triggered paracrinally when high sodium levels are detected via the epithelial sodium channel (ENaC). The primary activation factor of CNTGF–whether NaCl concentration, independent luminal flow, or the combined total sodium delivery–is still unclear. We hypothesized that increasing luminal flow in the CNT induces CNTGF via O2- generation and ENaC activation. Methods: Rabbit afferent arterioles (Af-Arts) with adjacent CNTs were microperfused ex-vivo with variable flow rates and sodium concentrations ranging from <1 mM to 80 mM and from 5 to 40 nL/min flow rates. Results: Perfusion of the CNT with 5 mM NaCl and increasing flow rates from 5 to 10, 20, and 40 nL/min caused a flow rate-dependent dilation of the Af-Art (p<0.001). Adding the ENaC blocker benzamil inhibited flow-induced Af-Art dilation, indicating a CNTGF response. In contrast, perfusion of the CNT with <1 mM NaCl did not result in flow-induced CNTGF vasodilation (p>0.05). Multiple linear regression modeling (R2=0.51;p<0.001) demonstrated that tubular flow (β=0.163 ± 0.04;p<0.001) and sodium concentration (β=0.14 ± 0.03;p<0.001) are independent variables that induce afferent arteriole vasodilation. Tempol reduced flow-induced CNTGF, and L-NAME did not influence this effect. Conclusion: Increased luminal flow in the CNT induces CNTGF activation via ENaC, partially due to flow-stimulated O2- production and independent of nitric oxide synthase (NOS) activity.
{"title":"Luminal Flow in the Connecting Tubule induces Afferent Arteriole Vasodilation","authors":"Hong Wang, Pablo A Ortiz, Cesar A Romero","doi":"10.1101/2024.09.12.612758","DOIUrl":"https://doi.org/10.1101/2024.09.12.612758","url":null,"abstract":"Background: Renal autoregulatory mechanisms modulate renal blood flow. Connecting tubule glomerular feedback (CNTGF) is a vasodilator mechanism in the connecting tubule (CNT), triggered paracrinally when high sodium levels are detected via the epithelial sodium channel (ENaC). The primary activation factor of CNTGF–whether NaCl concentration, independent luminal flow, or the combined total sodium delivery–is still unclear. We hypothesized that increasing luminal flow in the CNT induces CNTGF via O2- generation and ENaC activation. Methods: Rabbit afferent arterioles (Af-Arts) with adjacent CNTs were microperfused ex-vivo with variable flow rates and sodium concentrations ranging from <1 mM to 80 mM and from 5 to 40 nL/min flow rates. Results: Perfusion of the CNT with 5 mM NaCl and increasing flow rates from 5 to 10, 20, and 40 nL/min caused a flow rate-dependent dilation of the Af-Art (p<0.001). Adding the ENaC blocker benzamil inhibited flow-induced Af-Art dilation, indicating a CNTGF response. In contrast, perfusion of the CNT with <1 mM NaCl did not result in flow-induced CNTGF vasodilation (p>0.05). Multiple linear regression modeling (R2=0.51;p<0.001) demonstrated that tubular flow (β=0.163 ± 0.04;p<0.001) and sodium concentration (β=0.14 ± 0.03;p<0.001) are independent variables that induce afferent arteriole vasodilation. Tempol reduced flow-induced CNTGF, and L-NAME did not influence this effect. Conclusion: Increased luminal flow in the CNT induces CNTGF activation via ENaC, partially due to flow-stimulated O2- production and independent of nitric oxide synthase (NOS) activity.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1101/2024.09.12.612720
Maria Correia, Elisa Thoral, Elin Persson, Eskil Elmer, Imen Chamkha, Andreas Nord
Research on birds suggests that extreme weather events during development may have long-lasting consequences on form and function. The underlying cellular mechanisms mediating such phenotypic effects are poorly studied. We raised Japanese quail in warm (30oC) or cold (10oC) temperatures from hatching until adulthood, and then measured mitochondrial metabolism in intact blood cells at representative normothermic body temperature (41oC) and a hyperthermic temperature (45oC) that quail commonly attain when heat stressed. To investigate whether any developmental effects were reversible, half of the cold- and warm-acclimated birds were assigned to a common garden (20oC) 3 weeks before the measurements. Across groups, hyperthermia was associated with increased proton leak, but decreases in both phosphorylating respiration (where ATP is produced) and working capacity of the mitochondria. Cold-acclimated birds were more strongly affected by heat stress: the increase in proton leak was 1.6-fold higher, and the decrease in phosphorylating capacity during endogenous respiration was 1.7-fold greater, compared to warm-acclimated birds. These differences did not remain in the common-garden birds. Our study suggests that developmental cold acclimation is traded off against heat tolerance at the level of cellular metabolism, with implications for our understanding of avian responses to climate change.
{"title":"Development in the cold renders bird mitochondria more susceptible to heat stress","authors":"Maria Correia, Elisa Thoral, Elin Persson, Eskil Elmer, Imen Chamkha, Andreas Nord","doi":"10.1101/2024.09.12.612720","DOIUrl":"https://doi.org/10.1101/2024.09.12.612720","url":null,"abstract":"Research on birds suggests that extreme weather events during development may have long-lasting consequences on form and function. The underlying cellular mechanisms mediating such phenotypic effects are poorly studied. We raised Japanese quail in warm (30oC) or cold (10oC) temperatures from hatching until adulthood, and then measured mitochondrial metabolism in intact blood cells at representative normothermic body temperature (41oC) and a hyperthermic temperature (45oC) that quail commonly attain when heat stressed. To investigate whether any developmental effects were reversible, half of the cold- and warm-acclimated birds were assigned to a common garden (20oC) 3 weeks before the measurements. Across groups, hyperthermia was associated with increased proton leak, but decreases in both phosphorylating respiration (where ATP is produced) and working capacity of the mitochondria. Cold-acclimated birds were more strongly affected by heat stress: the increase in proton leak was 1.6-fold higher, and the decrease in phosphorylating capacity during endogenous respiration was 1.7-fold greater, compared to warm-acclimated birds. These differences did not remain in the common-garden birds. Our study suggests that developmental cold acclimation is traded off against heat tolerance at the level of cellular metabolism, with implications for our understanding of avian responses to climate change.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"74 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Uterine leiomyomas (UL) are the most prevalent benign tumors of the female reproductive tract, originating from the myometrium and affecting over 75% of reproductive-age women. Symptoms of UL include pelvic pain, pressure, dysmenorrhea, menorrhagia, anemia, and reproductive dysfunction. Currently, there is no effective long-term pharmacotherapy for UL, making them the leading cause of hysterectomies in the United States. The lack of treatment options is attributed to the absence of accurate animal models and a limited understanding of UL pathogenesis. Previous research has shown the loss of repressor of element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) within the myometrium promotes UL pathogenesis. In addition, deletion of Rest in the mouse myometrium leads to a UL phenotype. PRICKLE1, also known as Rest-interacting LIM-domain Protein (RILP), is required for nuclear localization of REST and Wnt/planar cell polarity (PCP) signaling, making it a critical target for UL studies. In the context of PCP, smooth muscle cells in UL show abnormal organization, aberrant ECM structure, and expression levels, potentially influenced by PRICKLE1 loss. The exact role of PRICKLE1 and Wnt/PCP in UL pathogenesis remains unclear. To explore PRICKLE1's role in UL, we deleted Prickle1 using our myometrial-specific icre. Our findings demonstrate that Prickle1 loss in the myometrium results in a UL phenotype characterized by altered collagen expression, excessive extracellular matrix (ECM) deposition, aberrant smooth muscle cell organization, increased Esr1 and Pgr expression, and dysregulated Wnt/PCP signaling. This novel mouse model serves as a valuable preclinical tool for understanding UL pathogenesis and developing future pharmacotherapies.
子宫肌瘤（UL）是女性生殖道中最常见的良性肿瘤，起源于子宫肌层，75% 以上的育龄妇女都会患上这种肿瘤。子宫肌瘤的症状包括盆腔疼痛、压痛、痛经、月经过多、贫血和生殖功能障碍。目前，UL 尚无有效的长期药物治疗方法，因此成为美国子宫切除术的主要病因。缺乏治疗方案的原因在于缺乏准确的动物模型以及对 UL 发病机制的了解有限。先前的研究表明，子宫肌层中 1 号元素沉默转录因子/神经元限制沉默因子（REST/NRSF）的缺失会促进 UL 的发病。此外，在小鼠子宫肌层中缺失 Rest 会导致 UL 表型。PRICKLE1又称Rest-interacting LIM-domain Protein (RILP)，是REST核定位和Wnt/平面细胞极性（PCP）信号传导所必需的，因此成为UL研究的关键靶点。在 PCP 的背景下，UL 中的平滑肌细胞显示出异常的组织、异常的 ECM 结构和表达水平，这可能受到 PRICKLE1 缺失的影响。PRICKLE1和Wnt/PCP在UL发病机制中的确切作用仍不清楚。为了探索PRICKLE1在UL中的作用，我们使用子宫肌特异性icre删除了Prickle1。我们的研究结果表明，子宫肌层中 Prickle1 的缺失会导致以胶原表达改变、细胞外基质（ECM）过度沉积、平滑肌细胞组织异常、Esr1 和 Pgr 表达增加以及 Wnt/PCP 信号传导失调为特征的 UL 表型。这种新型小鼠模型是了解 UL 发病机制和开发未来药物疗法的宝贵临床前工具。
{"title":"Loss of PRICKLE1 in the myometrium leads to reduced fertility, abnormal myometrial architecture, and aberrant extracellular matrix deposition in mice.","authors":"Emily Roberts, Sornakala Ganeshkumar, Sumedha Gunewardena, Vargheese Mani Chennathukuzhi","doi":"10.1101/2024.09.12.612708","DOIUrl":"https://doi.org/10.1101/2024.09.12.612708","url":null,"abstract":"Uterine leiomyomas (UL) are the most prevalent benign tumors of the female reproductive tract, originating from the myometrium and affecting over 75% of reproductive-age women. Symptoms of UL include pelvic pain, pressure, dysmenorrhea, menorrhagia, anemia, and reproductive dysfunction. Currently, there is no effective long-term pharmacotherapy for UL, making them the leading cause of hysterectomies in the United States. The lack of treatment options is attributed to the absence of accurate animal models and a limited understanding of UL pathogenesis. Previous research has shown the loss of repressor of element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) within the myometrium promotes UL pathogenesis. In addition, deletion of <em>Rest</em> in the mouse myometrium leads to a UL phenotype. PRICKLE1, also known as Rest-interacting LIM-domain Protein (RILP), is required for nuclear localization of REST and Wnt/planar cell polarity (PCP) signaling, making it a critical target for UL studies. In the context of PCP, smooth muscle cells in UL show abnormal organization, aberrant ECM structure, and expression levels, potentially influenced by PRICKLE1 loss. The exact role of PRICKLE1 and Wnt/PCP in UL pathogenesis remains unclear. To explore PRICKLE1's role in UL, we deleted <em>Prickle1</em> using our myometrial-specific icre. Our findings demonstrate that <em>Prickle1</em> loss in the myometrium results in a UL phenotype characterized by altered collagen expression, excessive extracellular matrix (ECM) deposition, aberrant smooth muscle cell organization, increased <em>Esr1</em> and <em>Pgr</em> expression, and dysregulated Wnt/PCP signaling. This novel mouse model serves as a valuable preclinical tool for understanding UL pathogenesis and developing future pharmacotherapies.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1101/2024.09.10.612372
Yuan Yi, Yu Yan, Guowu Liu, Chuang Cui, Yanhua Zhai, Ke Xu, Xinjun He
Psoriasis is an immune mediated, chronic inflammatory skin disease. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have inherent immunomodulatory potency from their parental cells, the mesenchymal stem cells (MSCs). In this study, we revealed the application potential of MSC-EVs to alleviate psoriatic symptoms in imiquimod-induced psoriasis mouse model.
{"title":"Mesenchymal stem cell-derived extracellular vesicles alleviate imiquimod-induced psoriasis symptoms in a mouse disease model","authors":"Yuan Yi, Yu Yan, Guowu Liu, Chuang Cui, Yanhua Zhai, Ke Xu, Xinjun He","doi":"10.1101/2024.09.10.612372","DOIUrl":"https://doi.org/10.1101/2024.09.10.612372","url":null,"abstract":"Psoriasis is an immune mediated, chronic inflammatory skin disease. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have inherent immunomodulatory potency from their parental cells, the mesenchymal stem cells (MSCs). In this study, we revealed the application potential of MSC-EVs to alleviate psoriatic symptoms in imiquimod-induced psoriasis mouse model.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"105 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1101/2024.09.12.612627
Hiba J Tannous, Corine J Samaha, Hassan A Chami, Joseph G Ghafari, Jason Amatoury
Background: Mandibular advancement serves as a treatment option for obstructive sleep apnea (OSA), but its effectiveness differs among patients. The position of the hyoid bone is crucial for maintaining upper airway patency and may influence mandibular advancement outcomes. This study aimed to assess the impact of surgical hyoid re-positioning on mandibular advancement-induced changes in upper airway collapsibility in an animal model. Methods: Twelve anesthetized male New Zealand White rabbits underwent mandibular advancement (0-4mm), combined with hyoid repositioning in various directions (anterior, cranial, caudal, anterior-cranial, anterior-caudal) and increments (0-4mm). Upper airway collapsibility was quantified as the negative pressure required to close the airway (Pclose) at various mandibular and hyoid positions. Results: Increasing mandibular advancement alone led to a progressive reduction in Pclose, indicating a decrease in upper airway collapsibility. Similarly, anterior hyoid repositioning alone resulted in incremental reductions in Pclose, with similar outcomes observed for anterior-cranial and anterior-caudal directions. When mandibular advancement was combined with anterior-based hyoid repositioning directions, a further decrease in Pclose was observed compared to when either intervention was applied alone. Cranial and caudal hyoid repositioning had no direct effect on Pclose or on mandibular advancement outcomes. Conclusions: In summary, decreases in upper airway collapsibility induced by mandibular advancement are dependent on both hyoid repositioning direction and increment. The findings suggest that combining mandibular advancement with anterior-based hyoid repositioning may enhance the effectiveness of mandibular advancement in treating OSA.
背景：下颌前突是治疗阻塞性睡眠呼吸暂停（OSA）的一种方法，但其效果因患者而异。舌骨的位置对维持上气道通畅至关重要，可能会影响下颌前突矫正术的效果。本研究旨在动物模型中评估手术舌骨重新定位对下颌前突引起的上气道塌陷变化的影响。方法：12 只麻醉后的雄性新西兰白兔接受了下颌骨前移术（0-4 毫米），同时在不同方向（前方、头颅、尾部、前-头颅、前-尾部）和增量（0-4 毫米）进行了舌骨复位。上气道塌陷度被量化为在不同下颌骨和舌骨位置时关闭气道所需的负压（Pclose）。结果：仅增加下颌前突就会导致Pclose逐渐降低，表明上气道塌陷度降低。同样，单纯的舌骨前方复位也会导致 Pclose 值逐渐降低，在前颅方向和前臀方向观察到的结果类似。当下颌骨前移与舌骨前方复位方向结合使用时，与单独使用其中一种干预方法相比，Pclose值进一步降低。头颅和尾部的舌骨复位对Pclose和下颌骨前移的结果没有直接影响。结论：总之，下颌前突引起的上气道塌陷度下降取决于舌骨复位的方向和增量。研究结果表明，将下颌前移术与舌骨前方复位术结合使用，可提高下颌前移术治疗 OSA 的效果。
{"title":"Surgical hyoid bone repositioning effects on mandibular advancement and upper airway collapsibility","authors":"Hiba J Tannous, Corine J Samaha, Hassan A Chami, Joseph G Ghafari, Jason Amatoury","doi":"10.1101/2024.09.12.612627","DOIUrl":"https://doi.org/10.1101/2024.09.12.612627","url":null,"abstract":"Background: Mandibular advancement serves as a treatment option for obstructive sleep apnea (OSA), but its effectiveness differs among patients. The position of the hyoid bone is crucial for maintaining upper airway patency and may influence mandibular advancement outcomes. This study aimed to assess the impact of surgical hyoid re-positioning on mandibular advancement-induced changes in upper airway collapsibility in an animal model. Methods: Twelve anesthetized male New Zealand White rabbits underwent mandibular advancement (0-4mm), combined with hyoid repositioning in various directions (anterior, cranial, caudal, anterior-cranial, anterior-caudal) and increments (0-4mm). Upper airway collapsibility was quantified as the negative pressure required to close the airway (Pclose) at various mandibular and hyoid positions. Results: Increasing mandibular advancement alone led to a progressive reduction in Pclose, indicating a decrease in upper airway collapsibility. Similarly, anterior hyoid repositioning alone resulted in incremental reductions in Pclose, with similar outcomes observed for anterior-cranial and anterior-caudal directions. When mandibular advancement was combined with anterior-based hyoid repositioning directions, a further decrease in Pclose was observed compared to when either intervention was applied alone. Cranial and caudal hyoid repositioning had no direct effect on Pclose or on mandibular advancement outcomes. Conclusions: In summary, decreases in upper airway collapsibility induced by mandibular advancement are dependent on both hyoid repositioning direction and increment. The findings suggest that combining mandibular advancement with anterior-based hyoid repositioning may enhance the effectiveness of mandibular advancement in treating OSA.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-14DOI: 10.1101/2024.09.12.612245
Gregoire Arnoux, Justine Serre, Thomas Verissimo, Matthieu Tihy, Sandrine Placier, Charles Verney, Frederic Sangla, Deborah Paolucci, Marylise Fernandez, Sophie de Seigneux, Sebastian Sgardello, Maarten Naesens, Juliette Hadchouel, Eric Feraille, Stellor Nlandu Khodo, Pierre Galichon, David Legouis
Acute kidney injury (AKI) is a prevalent and significant complication in critically ill patients, and its management remains a considerable challenge. The kidney is a highly metabolic organ, consuming and producing substantial amounts of ATP, mainly through mitochondrial oxidative phosphorylation. Recently, mitochondrial dysfunction has been identified as a key factor in the pathophysiology of AKI and the progression to chronic kidney disease. The kidney is a complex organ, comprising millions of structural and functional units. These nephrons are composed of different cell types dwelling within specific metabolic microenvironment. Whether the metabolic spatialization in the kidney has consequences on tubular injury distribution and severity remains unclear. In this study, we identified the high metabolic rate of the outer stripe of the outer medulla (OSOM) and its substrate preference flexibility, relying on both glycolysis and fatty acid oxidation (FAO) to fulfill its ATP demands. We demonstrated that the OSOM is susceptible to mitochondrial and FAO impairment induced by propofol, the most used sedative in intensive care settings, which exacerbates tubular injury during AKI. In the clinical setting, the cumulative dose of propofol is positively correlated with oxidative metabolism disruption and histological and function outcomes in renal allograft recipients. Finally, we found that the loop of Henle, the OSOM major constituent, was the most injured segment during AKI in patients. This study shows how renal metabolic spatialization impacts tubular injury severity. We identified the OSOM as the most metabolically active and the most injured region of the kidney both in humans and mice. We demonstrated that propofol is a potent inhibitor of renal mitochondrial function and FAO exacerbating tubular injury in the OSOM upon IRI.
急性肾损伤（AKI）是危重病人普遍存在的一种严重并发症，其治疗仍然是一个相当大的挑战。肾脏是一个高代谢器官，主要通过线粒体氧化磷酸化消耗和产生大量的 ATP。最近，线粒体功能障碍已被确定为 AKI 病理生理学和慢性肾脏病进展的关键因素。肾脏是一个复杂的器官，由数百万个结构和功能单元组成。这些肾小球由居住在特定代谢微环境中的不同细胞类型组成。在这项研究中，我们发现了外髓质外侧条纹（OSOM）的高代谢率及其底物偏好的灵活性，它依靠糖酵解和脂肪酸氧化（FAO）来满足其对 ATP 的需求。我们证实，OSOM 易受重症监护环境中最常用的镇静剂异丙酚诱导的线粒体和 FAO 损伤的影响，而异丙酚会加重 AKI 期间的肾小管损伤。在临床环境中，异丙酚的累积剂量与氧化代谢紊乱、肾移植受者的组织学和功能结果呈正相关。最后，我们发现，OSOM 的主要组成部分亨勒襻是患者在 AKI 期间损伤最严重的节段。我们发现 OSOM 是人类和小鼠肾脏中代谢最活跃和损伤最严重的区域。我们证明了异丙酚是肾线粒体功能和FAO的强效抑制剂，会在IRI时加重OSOM的肾小管损伤。
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Pub Date : 2024-09-14DOI: 10.1101/2024.09.11.612414
Jun-Ichi Sakagami, Ibrahim Soe, Emmanuel Odama, Rael Chepkoech, Taiichiro Ookawa, Abdelbagi M. Ismail
Flooding and drought significantly reduce rice yield in rainfed environments. Rice varieties that tolerate complete inundation for up to two weeks carry the SUB1A gene, while those enduring deeper water conditions for weeks or months have the SK1 and SK2 genes. Conversely, the DRO1 gene, responsible for deep-rooting, helps in water acquisition under drought. In this study, we compared the growth of NIL-SUB1DRO1 a novel rice genotype with an IR64 background regarding its dual tolerance to submergence and drought. Additionally, we assessed its recovery capacity after exposure to stress. Sixteen and thirteen-days old seedlings of three genotypes (Experiment 1-1 and 2-1) and fourteen-days old seedlings of the two genotypes (Experiment 1-2 and 2-2) were tested under submergence and drought stress in a greenhouse experimental condition respectively. Seedlings were submerged for 10 and 7 days and then allowed to recover for 10 and 7 days respectively. In the drought experiment, seedlings underwent 29 days of drought (Experiment 2-1) and 18 days of drought, followed by 10 days of rewatering (Experiment 2-2). Growth parameters were measured before and after treatment, 4 days after submergence in experiment 1-1 and after the recovery periods. Submergence and drought adversely affected growth and performance. Shoot elongation in submerged plants was reduced by 29.2% for NIL-SUB1DRO1 compared to IR64. Accelerated shoot elongation of IR64 negatively affected its recovery. Chlorophyll content and maximum fluorescence of IR64 were significantly lower than other genotypes after 10 and 7 days of complete submergence. Ten days after recovery in experiment 1-1 the Chlorophyll content and maximum fluorescence of IR64 were not significantly different compared to other genotypes. Seven days after of recovery in experiment 1-2, NIL-SUB1DRO1 had significantly higher chlorophyll content and maximum fluorescence than IR64. After 29 days of drought the tiller number and leaf area of IR64 was lower than other genotypes (Experiment 2-1), while in Experiment 2-2 during drought treatment and recovery, NIL-SUB1DRO1 had greater relative water content, leaf water potential, leaf area, SPAD value, dry weights of shoots and roots, root length, surface area and volume compared to IR64. stomatal conductance of IR64 was higher than NIL-SUB1DRO1 during drought, leading to greater water loss and reduced growth during recovery. NIL-SUB1DRO1 absorbed and retained water more effectively under dry conditions. NIL-SUB1DRO1 and NIL-SUB1 is tolerant to submergence and NIL-SUB1DRO1 and NIL-DRO1 to drought, with no negative effects from combining these genes in modern rice varieties for rainfed lowlands.
{"title":"Evaluation of stress tolerance in IR64 rice near-isogenic lines carrying SUB1 and DRO1 genes","authors":"Jun-Ichi Sakagami, Ibrahim Soe, Emmanuel Odama, Rael Chepkoech, Taiichiro Ookawa, Abdelbagi M. Ismail","doi":"10.1101/2024.09.11.612414","DOIUrl":"https://doi.org/10.1101/2024.09.11.612414","url":null,"abstract":"Flooding and drought significantly reduce rice yield in rainfed environments. Rice varieties that tolerate complete inundation for up to two weeks carry the SUB1A gene, while those enduring deeper water conditions for weeks or months have the SK1 and SK2 genes. Conversely, the DRO1 gene, responsible for deep-rooting, helps in water acquisition under drought. In this study, we compared the growth of NIL-SUB1DRO1 a novel rice genotype with an IR64 background regarding its dual tolerance to submergence and drought. Additionally, we assessed its recovery capacity after exposure to stress. Sixteen and thirteen-days old seedlings of three genotypes (Experiment 1-1 and 2-1) and fourteen-days old seedlings of the two genotypes (Experiment 1-2 and 2-2) were tested under submergence and drought stress in a greenhouse experimental condition respectively. Seedlings were submerged for 10 and 7 days and then allowed to recover for 10 and 7 days respectively. In the drought experiment, seedlings underwent 29 days of drought (Experiment 2-1) and 18 days of drought, followed by 10 days of rewatering (Experiment 2-2). Growth parameters were measured before and after treatment, 4 days after submergence in experiment 1-1 and after the recovery periods. Submergence and drought adversely affected growth and performance. Shoot elongation in submerged plants was reduced by 29.2% for NIL-SUB1DRO1 compared to IR64. Accelerated shoot elongation of IR64 negatively affected its recovery. Chlorophyll content and maximum fluorescence of IR64 were significantly lower than other genotypes after 10 and 7 days of complete submergence. Ten days after recovery in experiment 1-1 the Chlorophyll content and maximum fluorescence of IR64 were not significantly different compared to other genotypes. Seven days after of recovery in experiment 1-2, NIL-SUB1DRO1 had significantly higher chlorophyll content and maximum fluorescence than IR64. After 29 days of drought the tiller number and leaf area of IR64 was lower than other genotypes (Experiment 2-1), while in Experiment 2-2 during drought treatment and recovery, NIL-SUB1DRO1 had greater relative water content, leaf water potential, leaf area, SPAD value, dry weights of shoots and roots, root length, surface area and volume compared to IR64. stomatal conductance of IR64 was higher than NIL-SUB1DRO1 during drought, leading to greater water loss and reduced growth during recovery. NIL-SUB1DRO1 absorbed and retained water more effectively under dry conditions. NIL-SUB1DRO1 and NIL-SUB1 is tolerant to submergence and NIL-SUB1DRO1 and NIL-DRO1 to drought, with no negative effects from combining these genes in modern rice varieties for rainfed lowlands.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-14DOI: 10.1101/2024.09.13.612358
Beth M Wiese, Evgeny Bondarenko, Jack L. Feldman
Using a mouse equivalent of FDA-approved cannabidiol (CBD) dosing, we found high dose CBD affects opioid induced persistent apnea (OIPA), the principal cause of opioid related fatalities. CBD pretreatment mitigated respiratory depression from fentanyl in awake mice and significantly delayed OIPA onset in anesthetized mice, effective as the opioid antagonist naloxone. The powerful effect of CBD pretreatment on OIPA suggests a novel therapeutic strategy to reduce fatal opioid overdose incidence.
{"title":"Proof of Concept for High-Dose Cannabidiol Pretreatment to Antagonize Opioid Induced Persistent Apnea","authors":"Beth M Wiese, Evgeny Bondarenko, Jack L. Feldman","doi":"10.1101/2024.09.13.612358","DOIUrl":"https://doi.org/10.1101/2024.09.13.612358","url":null,"abstract":"Using a mouse equivalent of FDA-approved cannabidiol (CBD) dosing, we found high dose CBD affects opioid induced persistent apnea (OIPA), the principal cause of opioid related fatalities. CBD pretreatment mitigated respiratory depression from fentanyl in awake mice and significantly delayed OIPA onset in anesthetized mice, effective as the opioid antagonist naloxone. The powerful effect of CBD pretreatment on OIPA suggests a novel therapeutic strategy to reduce fatal opioid overdose incidence.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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