bioRxiv - Pathology最新文献

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}