Mosquito saliva plays a determining role in flavivirus transmission. Here, we discover and elucidate how salivary lipids enhance transmission. Building upon our discovery of salivary extracellular vesicles (EV), we determined that lipids within mosquito EVs, and neither within human EVs nor virions, enhance infection for flaviviruses in primary cell types relevant for transmission. Mechanistically, mosquito EV-lipids specifically promote viral protein levels by reducing ER-associated degradation. Infection enhancement is caused by sphingomyelins within mosquito salivary EVs that elevate sphingomyelin concentration within host cells. Transmission assays showed that mosquito EV-lipids exacerbate disease severity. Our study reveals that EV-associated sphingomyelins within mosquito saliva enhance transmission for multiple flaviviruses by reconfiguring the host lipidome to promote viral protein levels and the resulting skin infection. Our findings open a new dimension centered on lipids in the interplay between hosts, mosquitoes and flaviviruses that determine transmission, unveiling lipids as a new pan-flavivirus target.
蚊子唾液在黄病毒传播中起着决定性作用。在这里，我们发现并阐明了唾液脂质是如何促进传播的。在发现唾液细胞外囊泡（EV）的基础上，我们确定蚊子EV中的脂质（人类EV或病毒中的脂质）能增强黄病毒在与传播相关的主要细胞类型中的感染。从机理上讲，蚊子EV脂质通过减少与ER相关的降解，特异性地提高了病毒蛋白水平。蚊子唾液 EV 中的鞘磷脂提高了宿主细胞内鞘磷脂的浓度，从而导致感染增强。传播试验表明，蚊子 EV 脂类会加剧疾病的严重程度。我们的研究揭示，蚊子唾液中的 EV 相关鞘磷脂通过重新配置宿主脂质体，提高病毒蛋白水平，并导致皮肤感染，从而增强多种黄病毒的传播。我们的研究结果开辟了一个新的维度，即在宿主、蚊子和黄病毒之间的相互作用中，以脂类为中心来决定传播，从而揭示了脂类是泛黄病毒的新靶点。
{"title":"Sphingomyelins in mosquito saliva modify the host lipidome to enhance transmission of flaviviruses by promoting viral protein levels","authors":"Hacene Medkour, Lauryne Pruvost, Xiaqian Gong, Virginie Vaissayre, Pascal Boutinaud, Justine Revel, Atitaya Hitakarun, Wannap Sornjai, Jim Zoladek, Duncan Richard Smith, Sebastien Nisole, Esther Nolte-t Hoen, Justine bertrand-Michel, Dorothee Misse, Guillaume Marti, Julien Pompon","doi":"10.1101/2024.06.14.599058","DOIUrl":"https://doi.org/10.1101/2024.06.14.599058","url":null,"abstract":"Mosquito saliva plays a determining role in flavivirus transmission. Here, we discover and elucidate how salivary lipids enhance transmission. Building upon our discovery of salivary extracellular vesicles (EV), we determined that lipids within mosquito EVs, and neither within human EVs nor virions, enhance infection for flaviviruses in primary cell types relevant for transmission. Mechanistically, mosquito EV-lipids specifically promote viral protein levels by reducing ER-associated degradation. Infection enhancement is caused by sphingomyelins within mosquito salivary EVs that elevate sphingomyelin concentration within host cells. Transmission assays showed that mosquito EV-lipids exacerbate disease severity. Our study reveals that EV-associated sphingomyelins within mosquito saliva enhance transmission for multiple flaviviruses by reconfiguring the host lipidome to promote viral protein levels and the resulting skin infection. Our findings open a new dimension centered on lipids in the interplay between hosts, mosquitoes and flaviviruses that determine transmission, unveiling lipids as a new pan-flavivirus target.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141530862","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 : 2024-06-04DOI: 10.1101/2024.05.30.596635
Jean-Marie Launay, Nicolas Vodovar
Autism spectrum disorder (ASD) is a complex and heterogeneous neurodevelopmental disorder. Contrary to what has been reported for genetics and gut dysbiosis, ASD appears to be very homogeneous when considering tryptophan metabolism. Indeed, multiple biochemical anomalies have been observed in most individuals with ASD. Following up on these findings, we found that ASD is strongly associated with the miscompartmentalization of the chemical chaperone trimethylamine N-oxide (TMAO). Intracellular TMAO was markedly reduced in individuals with ASD as a result of altered fluid/electrolyte homeostasis and was responsible for numerous biochemical anomalies described in ASD. Administration of urea in a rat model of ASD that recapitulates the biochemical anomalies observed in humans not only restored biochemical parameters but also broadly improved all behaviours. Our results demonstrate the major role of TMAO in the pathophysiology of ASD and cellular physiology, although TMAO miscompartmentalization is not causal for ASD. We anticipate that urea, which is already clinically approved, offers a breakthrough therapeutic opportunity for ASD.
{"title":"TMAO miscompartmentalization is a reversible driver of autism pathophysiology","authors":"Jean-Marie Launay, Nicolas Vodovar","doi":"10.1101/2024.05.30.596635","DOIUrl":"https://doi.org/10.1101/2024.05.30.596635","url":null,"abstract":"Autism spectrum disorder (ASD) is a complex and heterogeneous neurodevelopmental disorder. Contrary to what has been reported for genetics and gut dysbiosis, ASD appears to be very homogeneous when considering tryptophan metabolism. Indeed, multiple biochemical anomalies have been observed in most individuals with ASD. Following up on these findings, we found that ASD is strongly associated with the miscompartmentalization of the chemical chaperone trimethylamine N-oxide (TMAO). Intracellular TMAO was markedly reduced in individuals with ASD as a result of altered fluid/electrolyte homeostasis and was responsible for numerous biochemical anomalies described in ASD. Administration of urea in a rat model of ASD that recapitulates the biochemical anomalies observed in humans not only restored biochemical parameters but also broadly improved all behaviours. Our results demonstrate the major role of TMAO in the pathophysiology of ASD and cellular physiology, although TMAO miscompartmentalization is not causal for ASD. We anticipate that urea, which is already clinically approved, offers a breakthrough therapeutic opportunity for ASD.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141258824","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 : 2024-06-03DOI: 10.1101/2024.05.31.596515
Isabella Sellmer Ramos, Monica O Caldeira, Scott E Poock, Joao GN Moraes, Matthew C Lucy, Amanda L Patterson
Optimal reproductive success following parturition in lactating dairy cows is dependent upon adequate completion of uterine involution. Failure to resolve pathogenic bacterial contamination within the first week postpartum can lead to uterine disease (metritis). Metritis is associated with decreased fertility and a failure or delay to establish pregnancy. We hypothesized that the inflammation resulting from early postpartum metritis would be associated with long-term changes in uterine morphology due to impaired uterine involution within the first 30 days postpartum (dpp). First parity Holstein cows were diagnosed with or without metritis at 7-10 dpp and uterine tissue were analyzed at 30 (Exp. 1), or 80 and 165 (Exp. 2) dpp for the presence of abnormal morphology, including abnormal invasion of endometrial glands and stroma into the myometrium (adenomyosis) using immunohistochemistry for FOXA2 (uterine gland specific marker) and presence of late postpartum endometrial fibrosis using masons trichrome stain (MTS). Severity of adenomyosis was determined by the number and size of adenomyotic foci, distance of foci from the endometrium-myometrium interface (EMI), and degree of fibrosis (MTS stain intensity). The presence, size, and distance from the EMI of adenomyotic foci were greater later postpartum and in cows with early postpartum diagnosis of metritis. Endometrial fibrosis was greater at the stratum basalis (at EMI) compared to the stratum compactum endometrium (near lumen) for all Exp. 2 cows, but greater endometrial fibrosis (regardless of endometrial region) was observed in cows that were diagnosed with metritis. Taken together, these data indicate that early postpartum metritis is associated with long-term modifications to the postpartum uterine morphology, including aberrant endometrial invasion into the myometrium (adenomyosis) and increased pathological fibrogenesis, leading to the presence of late postpartum endometrial fibrosis (scar tissue). Additionally, increased collagen fiber at the EMI suggests a correlation between the development of adenomyosis and fibrosis, which could possibly result from sustained endometrial inflammation caused by uterine disease.
{"title":"Adenomyosis and fibrosis define the morphological memory of the postpartum uterus of dairy cows previously exposed to metritis.","authors":"Isabella Sellmer Ramos, Monica O Caldeira, Scott E Poock, Joao GN Moraes, Matthew C Lucy, Amanda L Patterson","doi":"10.1101/2024.05.31.596515","DOIUrl":"https://doi.org/10.1101/2024.05.31.596515","url":null,"abstract":"Optimal reproductive success following parturition in lactating dairy cows is dependent upon adequate completion of uterine involution. Failure to resolve pathogenic bacterial contamination within the first week postpartum can lead to uterine disease (metritis). Metritis is associated with decreased fertility and a failure or delay to establish pregnancy. We hypothesized that the inflammation resulting from early postpartum metritis would be associated with long-term changes in uterine morphology due to impaired uterine involution within the first 30 days postpartum (dpp). First parity Holstein cows were diagnosed with or without metritis at 7-10 dpp and uterine tissue were analyzed at 30 (Exp. 1), or 80 and 165 (Exp. 2) dpp for the presence of abnormal morphology, including abnormal invasion of endometrial glands and stroma into the myometrium (adenomyosis) using immunohistochemistry for FOXA2 (uterine gland specific marker) and presence of late postpartum endometrial fibrosis using masons trichrome stain (MTS). Severity of adenomyosis was determined by the number and size of adenomyotic foci, distance of foci from the endometrium-myometrium interface (EMI), and degree of fibrosis (MTS stain intensity). The presence, size, and distance from the EMI of adenomyotic foci were greater later postpartum and in cows with early postpartum diagnosis of metritis. Endometrial fibrosis was greater at the stratum basalis (at EMI) compared to the stratum compactum endometrium (near lumen) for all Exp. 2 cows, but greater endometrial fibrosis (regardless of endometrial region) was observed in cows that were diagnosed with metritis. Taken together, these data indicate that early postpartum metritis is associated with long-term modifications to the postpartum uterine morphology, including aberrant endometrial invasion into the myometrium (adenomyosis) and increased pathological fibrogenesis, leading to the presence of late postpartum endometrial fibrosis (scar tissue). Additionally, increased collagen fiber at the EMI suggests a correlation between the development of adenomyosis and fibrosis, which could possibly result from sustained endometrial inflammation caused by uterine disease.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141258607","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 : 2024-06-03DOI: 10.1101/2024.06.03.597077
Yun-Shuang Fan, Yong Xu, Bin Wan, Wei Sheng, Chong Wang, Sofie Louise Valk, Huafu Chen
Background and Hypothesis: Schizophrenia is a neurodevelopmental condition with alterations in both sensory and association cortical areas. These alterations have been reported to follow structural connectivity patterning, and to occur in a system-level fashion. Here, we investigated whether pathological alterations of schizophrenia originated from an early disruption of cortical organization by using 7−17-years-old individuals with early-onset schizophrenia (EOS). Study Design: We estimated cortical thickness using T1-weighted structural MRI data from 95 patients with antipsychotic-naive first-episode EOS and 99 typically developing (TD) controls. We then computed structural covariance of cortical thickness and estimated system-level organizational axes by performing nonlinear dimensionality reduction techniques on covariance matrices for the EOS and TD groups. Finally, we tested for group differences between EOS and TD individuals in terms of both structural covariance and covariance distances along the systematic axis. Study Results: The first covariance gradient differentiated motor regions from other cortical areas. Similar to the macrostructural axis in adults, the second gradient axis in young TD discriminated anterior from posterior regions and was compressed in EOS patients relative to TD controls. In addition, patients showed increased structural covariance between two ends of the systematic axis, with increased geodesic distance of covarying regions between two ends. Conclusion: Our findings revealed a contracted organizational axis of cortical thickness in EOS patients, which was attributed to excessive distally coordinated changes between anterior and posterior regions of the cortex. Taken together, our study suggests a possible early disruption of system-level neurodevelopment in schizophrenia.
背景与假设：精神分裂症是一种神经发育性疾病，患者的感觉和联想皮质区域都会发生改变。据报道，这些改变遵循结构连接模式，并以系统级的方式发生。在此，我们以 7-17 岁的早发型精神分裂症（EOS）患者为研究对象，探讨精神分裂症的病理改变是否源于皮层组织的早期破坏。研究设计：我们利用95名未服用抗精神病药物的首发EOS患者和99名发育典型（TD）对照者的T1加权结构磁共振成像数据估算了皮层厚度。然后，我们通过对 EOS 组和 TD 组的协方差矩阵执行非线性降维技术，计算了皮质厚度的结构协方差，并估算了系统级组织轴。最后，我们从结构协方差和沿系统轴的协方差距离两方面检验了 EOS 和 TD 患者之间的群体差异。研究结果：第一个协方差梯度将运动区与其他皮层区域区分开来。与成人的宏观结构轴类似，年轻 TD 患者的第二梯度轴可区分前部和后部区域，而且相对于 TD 对照组，EOS 患者的第二梯度轴被压缩。此外，患者表现出系统轴两端之间的结构共变性增加，两端之间共变区域的大地距离增加。结论：我们的研究结果表明，EOS 患者皮层厚度的组织轴收缩，这归因于皮层前部和后部区域之间过度的远端协调变化。综上所述，我们的研究表明，精神分裂症患者的系统级神经发育可能受到了早期干扰。
{"title":"Contracted anterior-posterior systematic covariance of cortical thickness in early-onset schizophrenia","authors":"Yun-Shuang Fan, Yong Xu, Bin Wan, Wei Sheng, Chong Wang, Sofie Louise Valk, Huafu Chen","doi":"10.1101/2024.06.03.597077","DOIUrl":"https://doi.org/10.1101/2024.06.03.597077","url":null,"abstract":"Background and Hypothesis: Schizophrenia is a neurodevelopmental condition with alterations in both sensory and association cortical areas. These alterations have been reported to follow structural connectivity patterning, and to occur in a system-level fashion. Here, we investigated whether pathological alterations of schizophrenia originated from an early disruption of cortical organization by using 7−17-years-old individuals with early-onset schizophrenia (EOS). Study Design: We estimated cortical thickness using T1-weighted structural MRI data from 95 patients with antipsychotic-naive first-episode EOS and 99 typically developing (TD) controls. We then computed structural covariance of cortical thickness and estimated system-level organizational axes by performing nonlinear dimensionality reduction techniques on covariance matrices for the EOS and TD groups. Finally, we tested for group differences between EOS and TD individuals in terms of both structural covariance and covariance distances along the systematic axis. Study Results: The first covariance gradient differentiated motor regions from other cortical areas. Similar to the macrostructural axis in adults, the second gradient axis in young TD discriminated anterior from posterior regions and was compressed in EOS patients relative to TD controls. In addition, patients showed increased structural covariance between two ends of the systematic axis, with increased geodesic distance of covarying regions between two ends. Conclusion: Our findings revealed a contracted organizational axis of cortical thickness in EOS patients, which was attributed to excessive distally coordinated changes between anterior and posterior regions of the cortex. Taken together, our study suggests a possible early disruption of system-level neurodevelopment in schizophrenia.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141258829","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}
The polarisome complex at the hyphal tip fuels filamentous growth in diverse biphasic fungal pathogens. This multi-component complex, featuring the actin nucleator Bni1 and other factors, initiates actin polymerization, guiding biphasic fungal growth and host infection. How dynamic assembly of polarisome complex is achieved to support filamentous fungi that undergo multistage morphogenesis for host invasion remains unclear, including Magnaporthe oryzae, which undergoes multistage morphological transition during rice infection. Here, we identified that the scaffolder MoSpa2 remodeling actin cable networks, in space and time, by assembling the polarisome complex via phase separation, supporting Magnaporthe oryzae's polarized growth. Via N-terminal intrinsically disordered regions (IDRs), MoSpa2 first stimulates actin cable assembly through multivalent interactions with MoBni1 nucleator, and then also creates polarized actin cable bundles by F-actin association and a concurrent inhibition of cofilin-mediated F-actin depolymerization. MoSpa2 mutants exhibit impaired hyphal growth and reduced rice infection, underling its significance. This work elucidates the fundamental mechanisms underlying fungal morphogenesis, offering the potential for targeted interventions in pathogenesis.
{"title":"Phase-separating MoSpa2 Complex Organizes Actin Nucleation Center for M.oryzae Plant Infection","authors":"Danxia He, Yuan-Bao Li, Qianqian Ma, Li-Bo Han, Dingzhong Tang, Yansong Miao","doi":"10.1101/2024.05.31.596866","DOIUrl":"https://doi.org/10.1101/2024.05.31.596866","url":null,"abstract":"The polarisome complex at the hyphal tip fuels filamentous growth in diverse biphasic fungal pathogens. This multi-component complex, featuring the actin nucleator Bni1 and other factors, initiates actin polymerization, guiding biphasic fungal growth and host infection. How dynamic assembly of polarisome complex is achieved to support filamentous fungi that undergo multistage morphogenesis for host invasion remains unclear, including Magnaporthe oryzae, which undergoes multistage morphological transition during rice infection. Here, we identified that the scaffolder MoSpa2 remodeling actin cable networks, in space and time, by assembling the polarisome complex via phase separation, supporting Magnaporthe oryzae's polarized growth. Via N-terminal intrinsically disordered regions (IDRs), MoSpa2 first stimulates actin cable assembly through multivalent interactions with MoBni1 nucleator, and then also creates polarized actin cable bundles by F-actin association and a concurrent inhibition of cofilin-mediated F-actin depolymerization. MoSpa2 mutants exhibit impaired hyphal growth and reduced rice infection, underling its significance. This work elucidates the fundamental mechanisms underlying fungal morphogenesis, offering the potential for targeted interventions in pathogenesis.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141258541","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 : 2024-06-02DOI: 10.1101/2024.05.28.596363
Gani Kuttymuratov, Ardak P Ainakulov, Askar Ayaganov, Kuat P Oshakbayev, Arman Mirmanov, Daulet Zharasov, Zhandos Imanberdiev, Askar Taszhurekov, Bakhytzhan Abdimazhitov, Aruzhan Asanova, Tleuzhan Abdurakhman, Nurlybek Uderbayev, Arnagul Kalieva
Objective: To evaluate the effectiveness of en bloc transplantation of a donor kidney, ureters and part of the bladder to a recipient with simulated microcystis in an experimental trial. Methods: Study Design: a 29-day, open, pilot prospective experimental trial: 14 days constituted an adaptation period, 5 days for the interventions, and 10 days constituted an observation period. The study totally included ten White Landras sibling pigs, which were divided into 12 donors and 12 recipients. The pigs were 3-4 months old and weighing 35-45 kg of both sexes from the same sow to avoid transplant rejection. The pigs lived 7-9 days after transplantation before they were euthanized, and then there were performed macrovisual and histological investigations. Descriptive, inferential statistics, and calculation of percentages were used. The Local Ethics Committee of West Kazakhstan Medical University approved the study. Results: Eleven pigs survived the operation, but one pig died 10 hours after the operation. The cause of death was pulmonary embolism according to the pathological autopsy. In the eleven animals the kidney, ureters and part of the bladder transplanted as en block visually were filled with urine, full of blood, and tissue turgor was good. Visual inspection of the kidney and ureters was satisfactory, bright red. The implanted bladder had a red-burgundy color in all four cases. No anastomotic leakage was observed. A histological examination of the graft tissue on the 7-9 after-surgery days showed the preservation of blood flow in the tissues of the bladder and ureters. No total tissue necrosis was detected. Conclusions: In our experimental model, transplantation of a donor kidney, ureters and part of the bladder to a recipient with a simulated microcyst is effectively feasible. Pigs are a relevant animal model for genitourinary organ transplantation.
{"title":"Transplantation of a kidney with a ureter and part of the bladder as a single block: an experimental study","authors":"Gani Kuttymuratov, Ardak P Ainakulov, Askar Ayaganov, Kuat P Oshakbayev, Arman Mirmanov, Daulet Zharasov, Zhandos Imanberdiev, Askar Taszhurekov, Bakhytzhan Abdimazhitov, Aruzhan Asanova, Tleuzhan Abdurakhman, Nurlybek Uderbayev, Arnagul Kalieva","doi":"10.1101/2024.05.28.596363","DOIUrl":"https://doi.org/10.1101/2024.05.28.596363","url":null,"abstract":"Objective: To evaluate the effectiveness of en bloc transplantation of a donor kidney, ureters and part of the bladder to a recipient with simulated microcystis in an experimental trial. Methods: Study Design: a 29-day, open, pilot prospective experimental trial: 14 days constituted an adaptation period, 5 days for the interventions, and 10 days constituted an observation period. The study totally included ten White Landras sibling pigs, which were divided into 12 donors and 12 recipients. The pigs were 3-4 months old and weighing 35-45 kg of both sexes from the same sow to avoid transplant rejection. The pigs lived 7-9 days after transplantation before they were euthanized, and then there were performed macrovisual and histological investigations. Descriptive, inferential statistics, and calculation of percentages were used. The Local Ethics Committee of West Kazakhstan Medical University approved the study. Results: Eleven pigs survived the operation, but one pig died 10 hours after the operation. The cause of death was pulmonary embolism according to the pathological autopsy. In the eleven animals the kidney, ureters and part of the bladder transplanted as en block visually were filled with urine, full of blood, and tissue turgor was good. Visual inspection of the kidney and ureters was satisfactory, bright red. The implanted bladder had a red-burgundy color in all four cases. No anastomotic leakage was observed. A histological examination of the graft tissue on the 7-9 after-surgery days showed the preservation of blood flow in the tissues of the bladder and ureters. No total tissue necrosis was detected. Conclusions: In our experimental model, transplantation of a donor kidney, ureters and part of the bladder to a recipient with a simulated microcyst is effectively feasible. Pigs are a relevant animal model for genitourinary organ transplantation.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141259058","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 : 2024-06-02DOI: 10.1101/2024.05.28.596301
Louis Barrows, Philip J Moos, Allison F Carey, Jacklyn Joseph, Stephanie Kialo, Joe Norrie, Julie M Moyarelce, Anthony Amof, Hans Nogua, Albebson L Lim
We successfully employed a single cell RNA sequencing (scRNA-seq) approach to describe the cells and the communication networks characterizing granulomatous lymph nodes of TB patients. When mapping cells from individual patient samples, clustered based on their transcriptome similarities, we uniformly identify several cell types that characterize human and non-human primate granulomas. Whether high or low Mtb burden, we find the T cell cluster to be one of the most abundant. Many cells expressing T cell markers are clearly quantifiable within this CD3 expressing cluster. Other cell clusters that are uniformly detected, but that vary dramatically in abundance amongst the individual patient samples, are the B cell, plasma cell and macrophage/dendrocyte and NK cell clusters. When we combine all our scRNA-seq data from our current 23 patients (in order to add power to cell cluster identification in patient samples with fewer cells), we distinguish T, macrophage, dendrocyte and plasma cell subclusters, each with distinct signaling activities. The sizes of these subclusters also varies dramatically amongst the individual patients. In comparing FNA composition we noted trends in which T cell populations and macrophage/dendrocyte populations were negatively correlated with NK cell populations. In addition, we also discovered that the scRNA-seq pipeline, designed for quantification of human cell mRNA, also detects Mtb RNA transcripts and associates them with their host cells transcriptome, thus identifying individual infected cells. We hypothesize that the number of detected bacterial transcript reads provides a measure of Mtb burden, as does the number of Mtb-infected cells. The number of infected cells also varies dramatically in abundance amongst the patient samples. CellChat analysis identified predominating signaling pathways amongst the cells comprising the various granulomas, including many interactions between stromal or endothelial cells, such as Collagen, FN1 and Laminin, and the other component cells. In addition, other more selective communications pathways, including MIF, MHC-1, MHC-2, APP, CD 22, CD45, and others, are identified as originating or being received by individual immune cell components.
我们成功地采用了单细胞 RNA 测序（scRNA-seq）方法来描述肺结核患者肉芽肿淋巴结的细胞和通讯网络特征。根据转录组的相似性对单个患者样本的细胞进行聚类后，我们一致确定了人类和非人灵长类肉芽肿的几种细胞类型。无论Mtb负担是高还是低，我们都发现T细胞群是最丰富的细胞群之一。在这个表达 CD3 的细胞群中，许多表达 T 细胞标记的细胞都可以清晰地量化。B 细胞、浆细胞、巨噬细胞/树突细胞和 NK 细胞群等其他细胞群的检测结果一致，但在患者样本中的丰度差异很大。当我们把目前 23 位患者的所有 scRNA-seq 数据合并在一起时（为了增加细胞较少的患者样本的细胞群识别能力），我们区分出了 T 细胞、巨噬细胞、树突状细胞和浆细胞亚群，每个亚群都有不同的信号活性。这些亚群的大小在不同患者之间也有很大差异。在比较 FNA 的组成时，我们注意到 T 细胞群和巨噬细胞/树突细胞群与 NK 细胞群呈负相关的趋势。此外，我们还发现，专为量化人体细胞 mRNA 而设计的 scRNA-seq 管道也能检测到 Mtb RNA 转录本，并将它们与宿主细胞转录组联系起来，从而识别出受感染的单个细胞。我们推测，检测到的细菌转录本读数数量和受 Mtb 感染的细胞数量一样，都是衡量 Mtb 负担的指标。患者样本中受感染细胞的数量也有很大差异。细胞聊天分析确定了组成各种肉芽肿的细胞之间的主要信号通路，包括基质或内皮细胞（如胶原蛋白、FN1 和层粘连蛋白）与其他组成细胞之间的许多相互作用。此外，其他更具选择性的通信途径，包括 MIF、MHC-1、MHC-2、APP、CD 22、CD45 等，也被确定为由单个免疫细胞成分产生或接收。
{"title":"Single Cell Analysis of Peripheral TB-Associated Granulomatous Lymphadenitis","authors":"Louis Barrows, Philip J Moos, Allison F Carey, Jacklyn Joseph, Stephanie Kialo, Joe Norrie, Julie M Moyarelce, Anthony Amof, Hans Nogua, Albebson L Lim","doi":"10.1101/2024.05.28.596301","DOIUrl":"https://doi.org/10.1101/2024.05.28.596301","url":null,"abstract":"We successfully employed a single cell RNA sequencing (scRNA-seq) approach to describe the cells and the communication networks characterizing granulomatous lymph nodes of TB patients. When mapping cells from individual patient samples, clustered based on their transcriptome similarities, we uniformly identify several cell types that characterize human and non-human primate granulomas. Whether high or low Mtb burden, we find the T cell cluster to be one of the most abundant. Many cells expressing T cell markers are clearly quantifiable within this CD3 expressing cluster. Other cell clusters that are uniformly detected, but that vary dramatically in abundance amongst the individual patient samples, are the B cell, plasma cell and macrophage/dendrocyte and NK cell clusters. When we combine all our scRNA-seq data from our current 23 patients (in order to add power to cell cluster identification in patient samples with fewer cells), we distinguish T, macrophage, dendrocyte and plasma cell subclusters, each with distinct signaling activities. The sizes of these subclusters also varies dramatically amongst the individual patients. In comparing FNA composition we noted trends in which T cell populations and macrophage/dendrocyte populations were negatively correlated with NK cell populations. In addition, we also discovered that the scRNA-seq pipeline, designed for quantification of human cell mRNA, also detects Mtb RNA transcripts and associates them with their host cells transcriptome, thus identifying individual infected cells. We hypothesize that the number of detected bacterial transcript reads provides a measure of Mtb burden, as does the number of Mtb-infected cells. The number of infected cells also varies dramatically in abundance amongst the patient samples. CellChat analysis identified predominating signaling pathways amongst the cells comprising the various granulomas, including many interactions between stromal or endothelial cells, such as Collagen, FN1 and Laminin, and the other component cells. In addition, other more selective communications pathways, including MIF, MHC-1, MHC-2, APP, CD 22, CD45, and others, are identified as originating or being received by individual immune cell components.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"312 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141258712","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 : 2024-06-02DOI: 10.1101/2024.05.30.596629
Haruka Hosoki, Toru Asahi, Chihiro Nozaki
It is known that cannabinoid type 2 (CB2) receptor has anti-inflammatory role, therefore animals without CB2 receptors shows enhanced inflammation and pain in the model of chronic pain e.g. neuropathic pain. We previously proposed the upregulated leptin signaling at the peripheral nerve as one of the underlying molecular mechanism of pain exacerbation in nerve-injured CB2 knockouts, as they displayed robust upregulation of leptin receptors and leptin signaling in peripheral nerve. Due to these past results we hypothesized that CB2 receptor deficiency might also modify the peripheral neuroinflammation lead by chronic exposure to high fat diet (HFD). Interestingly, CB2 knockout animals showed the significant resistance to the HFD-induced neuroinflammation. Namely, 5-week feeding of HFD induced substantial hypersensitivity in WT animals, while tactile sensitivity of HFD-fed CB2 knockouts remained intact. HFD-fed WT animals also displayed the robust upregulation of chemokine CXCR4 expression with increased macrophage infiltration, which was never observed in HFD-fed CB2 knockout mice. Moreover, 5-week HFD-exposure lead significant increase of splenic CD11b+Ly6G-Ly6Chigh cells and decrease of CD11b+Ly6G+Ly6Clow cells in WT animals, which was also not found in either HFD-fed CB2 knockouts or standard diet-fed WT and CB2 animals. These results together with past report suggest that CB2 receptors might have the double-sided regulatory role in context of the inflammation development, or more widely, immune system regulation. We propose that CB2 signaling is not always anti-inflammatory and could take pro-inflammatory role depending on the cause of the inflammation.
{"title":"Cannabinoid CB2 receptors enhance high-fat diet evoked peripheral neuroinflammation","authors":"Haruka Hosoki, Toru Asahi, Chihiro Nozaki","doi":"10.1101/2024.05.30.596629","DOIUrl":"https://doi.org/10.1101/2024.05.30.596629","url":null,"abstract":"It is known that cannabinoid type 2 (CB2) receptor has anti-inflammatory role, therefore animals without CB2 receptors shows enhanced inflammation and pain in the model of chronic pain e.g. neuropathic pain. We previously proposed the upregulated leptin signaling at the peripheral nerve as one of the underlying molecular mechanism of pain exacerbation in nerve-injured CB2 knockouts, as they displayed robust upregulation of leptin receptors and leptin signaling in peripheral nerve. Due to these past results we hypothesized that CB2 receptor deficiency might also modify the peripheral neuroinflammation lead by chronic exposure to high fat diet (HFD). Interestingly, CB2 knockout animals showed the significant resistance to the HFD-induced neuroinflammation. Namely, 5-week feeding of HFD induced substantial hypersensitivity in WT animals, while tactile sensitivity of HFD-fed CB2 knockouts remained intact. HFD-fed WT animals also displayed the robust upregulation of chemokine CXCR4 expression with increased macrophage infiltration, which was never observed in HFD-fed CB2 knockout mice. Moreover, 5-week HFD-exposure lead significant increase of splenic CD11b+Ly6G-Ly6Chigh cells and decrease of CD11b+Ly6G+Ly6Clow cells in WT animals, which was also not found in either HFD-fed CB2 knockouts or standard diet-fed WT and CB2 animals. These results together with past report suggest that CB2 receptors might have the double-sided regulatory role in context of the inflammation development, or more widely, immune system regulation. We propose that CB2 signaling is not always anti-inflammatory and could take pro-inflammatory role depending on the cause of the inflammation.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141258711","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 : 2024-06-01DOI: 10.1101/2024.05.27.596060
Robert C. McDonald, Andrew H. Fischer, Mary Rusckowski
An oxygen sensor-mounted fine-needle biopsy tool was used for in vivo measurement of oxygen levels in tumor xenografts. The system provides a means of measuring the oxygen content in harvested tumor tissue from specific locations. Oxygen in human tumor xenografts in a murine model was observed for over 1 min. Tissues were mapped in relation to oxygen tension (pO2) readings and sampled for conventional cytological examination. Careful modeling of the pO2 readings over 60 seconds yielded a diffusion coefficient for oxygen at the sensor tip, providing additional diagnostic information about the tissue before sampling. Oxygen level measurement may provide a useful adjunct to the use of biomarkers in tumor diagnosis.
{"title":"Oxygen Sensor-Guided Fine Needle Biopsy Studies of Human Cancer Xenografts in Mice","authors":"Robert C. McDonald, Andrew H. Fischer, Mary Rusckowski","doi":"10.1101/2024.05.27.596060","DOIUrl":"https://doi.org/10.1101/2024.05.27.596060","url":null,"abstract":"An oxygen sensor-mounted fine-needle biopsy tool was used for in vivo measurement of oxygen levels in tumor xenografts. The system provides a means of measuring the oxygen content in harvested tumor tissue from specific locations. Oxygen in human tumor xenografts in a murine model was observed for over 1 min. Tissues were mapped in relation to oxygen tension (pO2) readings and sampled for conventional cytological examination. Careful modeling of the pO2 readings over 60 seconds yielded a diffusion coefficient for oxygen at the sensor tip, providing additional diagnostic information about the tissue before sampling. Oxygen level measurement may provide a useful adjunct to the use of biomarkers in tumor diagnosis.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141198195","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 : 2024-06-01DOI: 10.1101/2024.05.27.596052
Sarah-Eve Lemay, Monica S Montesinos, Yann Grobs, Tetsuro Yokokawa, Tsukasa Shimauchi, Charlotte Romanet, Melanie Sauvaget, Sandra Breuils-Bonnet, Alice Bourgeois, Charlie Theberge, Adreanne Pelletier, Reem El Kabbout, Sandra Martineau, Keiko Yamamoto, Adrian S. Ray, Blaise Lippa, Bryan Goodwin, Fu-Yang Lin, Hua Wang, James E Dowling, Min Lu, Qi Qiao, Andrew McTeague, Terence I. Moy, Francois Potus, Steeve Provencher, Olivier Boucherat, Sebastien Bonnet
Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PA) and progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Although several drugs are approved for the treatment of PAH, mortality remains high. Accumulating evidence supports a pathological function of integrins in vessel remodeling, which are gaining renewed interest as drug targets. However, their role in PAH remains largely unexplored. We found that the arginine-glycine-aspartate (RGD)-binding integrin α5β1 is upregulated in PA endothelial cells (PAEC) and PA smooth muscle cells (PASMC) from PAH patients and remodeled PAs from animal models. Blockade of the integrin α5β1 or depletion of the α5 subunit resulted in mitotic defects and inhibition of the pro-proliferative and apoptosis-resistant phenotype of PAH cells. Using a novel small molecule integrin inhibitor and neutralizing antibodies, we demonstrated that α5β1 integrin blockade attenuates pulmonary vascular remodeling and improves hemodynamics and RV function in multiple preclinical models. Our results provide converging evidence to consider α5β1 integrin inhibition as a promising therapy for pulmonary hypertension.
肺动脉高压（PAH）的特点是肺小动脉（PA）血管闭塞性重塑和肺血管阻力（PVR）逐渐增加，导致右心室（RV）功能衰竭。虽然已有多种药物获准用于治疗 PAH，但死亡率仍然很高。越来越多的证据支持整合素在血管重塑中的病理功能，整合素作为药物靶点再次受到关注。然而，它们在 PAH 中的作用在很大程度上仍未被探索。我们发现，精氨酸-甘氨酸-天门冬氨酸（RGD）结合整合素α5β1在 PAH 患者的 PA 内皮细胞（PAEC）和 PA 平滑肌细胞（PASMC）以及动物模型重塑的 PA 中上调。阻断整合素 α5β1 或缺失 α5 亚基会导致 PAH 细胞有丝分裂缺陷，并抑制 PAH 细胞的促增殖和抗凋亡表型。我们使用一种新型小分子整合素抑制剂和中和抗体证明，在多个临床前模型中，α5β1 整合素阻断可减轻肺血管重塑，改善血液动力学和 RV 功能。我们的研究结果为将α5β1整合素抑制视为治疗肺动脉高压的一种有前景的疗法提供了汇聚证据。
{"title":"Exploring Integrin α5β1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights from Comprehensive Multicenter Preclinical Studies","authors":"Sarah-Eve Lemay, Monica S Montesinos, Yann Grobs, Tetsuro Yokokawa, Tsukasa Shimauchi, Charlotte Romanet, Melanie Sauvaget, Sandra Breuils-Bonnet, Alice Bourgeois, Charlie Theberge, Adreanne Pelletier, Reem El Kabbout, Sandra Martineau, Keiko Yamamoto, Adrian S. Ray, Blaise Lippa, Bryan Goodwin, Fu-Yang Lin, Hua Wang, James E Dowling, Min Lu, Qi Qiao, Andrew McTeague, Terence I. Moy, Francois Potus, Steeve Provencher, Olivier Boucherat, Sebastien Bonnet","doi":"10.1101/2024.05.27.596052","DOIUrl":"https://doi.org/10.1101/2024.05.27.596052","url":null,"abstract":"Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PA) and progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Although several drugs are approved for the treatment of PAH, mortality remains high. Accumulating evidence supports a pathological function of integrins in vessel remodeling, which are gaining renewed interest as drug targets. However, their role in PAH remains largely unexplored. We found that the arginine-glycine-aspartate (RGD)-binding integrin α5β1 is upregulated in PA endothelial cells (PAEC) and PA smooth muscle cells (PASMC) from PAH patients and remodeled PAs from animal models. Blockade of the integrin α5β1 or depletion of the α5 subunit resulted in mitotic defects and inhibition of the pro-proliferative and apoptosis-resistant phenotype of PAH cells. Using a novel small molecule integrin inhibitor and neutralizing antibodies, we demonstrated that α5β1 integrin blockade attenuates pulmonary vascular remodeling and improves hemodynamics and RV function in multiple preclinical models. Our results provide converging evidence to consider α5β1 integrin inhibition as a promising therapy for pulmonary hypertension.","PeriodicalId":501471,"journal":{"name":"bioRxiv - Pathology","volume":"65 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141198495","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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