Pub Date : 2024-07-16DOI: 10.1101/2024.07.11.603043
Jinyu Guo, Hui Yang, Chixiang Lu, Di Cui, Murong Zhao, Cun Li, Weihua Chen, Qian Yang, Zhijie Li, Mingkun Chen, Shanchao Zhao, Jie Zhou, Jiaye He, Haibo Jiang
Expansion microscopy (ExM) enhances the microscopy resolution by physically expanding biological specimens and improves the visualization of structural and molecular details. Numerous ExM techniques and labeling methods have been developed and refined over the past decade to cater to specific research needs. Nonetheless, a shared limitation among current protocols is the extensive time required for sample processing, particularly for challenging-to-expand biological specimens (e.g., formalin-fixed paraffin-embedded (FFPE) sections and large three-dimensional specimens). Here, we have developed a rapid and robust ExM workflow named BOOST, which leverages a series of novel microwave (MW)-accelerated ExM chemistry, resulting in a single-step linear expansion of ∼10×. Specifically, BOOST facilitates a ∼10-fold expansion of cultured cells, tissue sections, and even the challenging-to-expand FFPE sections under merely 90 minutes with heat and surfactant-based protein denaturation. Furthermore, BOOST employs microwave-assisted proteomic staining and immunostaining to facilitate high-resolution visualization of structural and molecular details with significantly enhanced throughput. Noteworthily, BOOST has pioneered a ∼10-fold expansion of large millimeter-sized three-dimensional specimens in approximately three hours. BOOST offers an easily adaptable workflow based on stable and common reagents, thus boosting the potential adoption of ExM methods in biological investigations.
{"title":"BOOST: a robust ten-fold expansion method on hour-scale","authors":"Jinyu Guo, Hui Yang, Chixiang Lu, Di Cui, Murong Zhao, Cun Li, Weihua Chen, Qian Yang, Zhijie Li, Mingkun Chen, Shanchao Zhao, Jie Zhou, Jiaye He, Haibo Jiang","doi":"10.1101/2024.07.11.603043","DOIUrl":"https://doi.org/10.1101/2024.07.11.603043","url":null,"abstract":"Expansion microscopy (ExM) enhances the microscopy resolution by physically expanding biological specimens and improves the visualization of structural and molecular details. Numerous ExM techniques and labeling methods have been developed and refined over the past decade to cater to specific research needs. Nonetheless, a shared limitation among current protocols is the extensive time required for sample processing, particularly for challenging-to-expand biological specimens (e.g., formalin-fixed paraffin-embedded (FFPE) sections and large three-dimensional specimens). Here, we have developed a rapid and robust ExM workflow named BOOST, which leverages a series of novel microwave (MW)-accelerated ExM chemistry, resulting in a single-step linear expansion of ∼10×. Specifically, BOOST facilitates a ∼10-fold expansion of cultured cells, tissue sections, and even the challenging-to-expand FFPE sections under merely 90 minutes with heat and surfactant-based protein denaturation. Furthermore, BOOST employs microwave-assisted proteomic staining and immunostaining to facilitate high-resolution visualization of structural and molecular details with significantly enhanced throughput. Noteworthily, BOOST has pioneered a ∼10-fold expansion of large millimeter-sized three-dimensional specimens in approximately three hours. BOOST offers an easily adaptable workflow based on stable and common reagents, thus boosting the potential adoption of ExM methods in biological investigations.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641170","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 : 2024-07-16DOI: 10.1101/2024.07.10.602969
K. C. Wynne, M. J. Parker-Smith, Erica M. Murdock, Lauren L. Sullivan
Seed rain is an influential process related to plant community diversity, composition, and regeneration. However, knowledge of seed rain patterns is limited to those observed in forests and late-assembling grasslands, which might not reflect early-assembling communities such as newly restored grasslands. Resolving this gap in our understanding provides further insight into the role of seed dispersal. Here, we measured seed rain in a remnant tallgrass prairie, which was the site of the foundational grassland seed rain study in 1978, and a nearby chronosequence of tallgrass prairie restorations. We sought to determine how the quantity, seed mass traits, timing, diversity, and composition of seed rain changed (1) long-term and (2) during community assembly. To do so, we deployed artificial turf grass seed traps into 2-year-old, 5-6-year-old, and 15-year-old restored prairies and the remnant prairie, replacing traps every two weeks from May to December 2019. We captured over twice the density and richness of seed rain in the remnant prairie in 2019 compared to 1978. We also found that seed rain patterns changed as prairies aged, with each prairie possessing a distinct community of dispersing species. Significantly more seeds, seed biomass, and species were captured in the youngest restored prairie. However, seed mass traits were similar in all prairies. Except for composition, all other seed rain metrics in the oldest restoration were eventually comparable to the remnant prairie. Synthesis and Applications: Our results revealed that grasslands, notably young prairies, produce larger quantities of seed rain than previously known (124,806 seeds m−2 year −1, 97.24 g m−2 year −1), and seed input in all sampled prairies far exceeded restoration broadcast seeding densities. We further found that decreases in seed rain quantity across the chronosequence did not correspond with increases in seed mass, suggesting a lack of tradeoffs between these metrics. Furthermore, tallgrass prairie restorations have not replicated the composition of seed rain seen in remnant systems. Increasing restoration seeding rates of desirable species may be needed to meet composition goals since current rates may not compete with the propagule pressure of undesirable species found in newly restored prairies.
{"title":"Quantifying seed rain patterns in a remnant and a chronosequence of restored tallgrass prairies in north central Missouri","authors":"K. C. Wynne, M. J. Parker-Smith, Erica M. Murdock, Lauren L. Sullivan","doi":"10.1101/2024.07.10.602969","DOIUrl":"https://doi.org/10.1101/2024.07.10.602969","url":null,"abstract":"Seed rain is an influential process related to plant community diversity, composition, and regeneration. However, knowledge of seed rain patterns is limited to those observed in forests and late-assembling grasslands, which might not reflect early-assembling communities such as newly restored grasslands. Resolving this gap in our understanding provides further insight into the role of seed dispersal. Here, we measured seed rain in a remnant tallgrass prairie, which was the site of the foundational grassland seed rain study in 1978, and a nearby chronosequence of tallgrass prairie restorations. We sought to determine how the quantity, seed mass traits, timing, diversity, and composition of seed rain changed (1) long-term and (2) during community assembly. To do so, we deployed artificial turf grass seed traps into 2-year-old, 5-6-year-old, and 15-year-old restored prairies and the remnant prairie, replacing traps every two weeks from May to December 2019. We captured over twice the density and richness of seed rain in the remnant prairie in 2019 compared to 1978. We also found that seed rain patterns changed as prairies aged, with each prairie possessing a distinct community of dispersing species. Significantly more seeds, seed biomass, and species were captured in the youngest restored prairie. However, seed mass traits were similar in all prairies. Except for composition, all other seed rain metrics in the oldest restoration were eventually comparable to the remnant prairie. Synthesis and Applications: Our results revealed that grasslands, notably young prairies, produce larger quantities of seed rain than previously known (124,806 seeds m−2 year −1, 97.24 g m−2 year −1), and seed input in all sampled prairies far exceeded restoration broadcast seeding densities. We further found that decreases in seed rain quantity across the chronosequence did not correspond with increases in seed mass, suggesting a lack of tradeoffs between these metrics. Furthermore, tallgrass prairie restorations have not replicated the composition of seed rain seen in remnant systems. Increasing restoration seeding rates of desirable species may be needed to meet composition goals since current rates may not compete with the propagule pressure of undesirable species found in newly restored prairies.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641159","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 : 2024-07-16DOI: 10.1101/2024.07.08.602437
Lei Ni, Yajia Huang, Yaoxin Huang, Yue Yu, Jiarui Xiong, Hui Wen, Wenwen Xiao, Haiyi Liang, Fan Jin
Bacteria employ various strategies to coordinate population-level behaviors, with quorum sensing being a well-established mechanism. Here, we report a novel population-level regulatory mechanism in Pseudomonas aeruginosa, which we term ‘pressorum sensing’. This mechanism allows bacteria to modulate their collective behavior in response to growth-induced mechanical compression in confined spaces. Using a highly sensitive cAMP biosensor in combination with microfluidics, we demonstrate that when compressive forces reach approximately 30 nN, P. aeruginosa cells rapidly increases intracellular cAMP levels via the Pil-Chp chemosensory system. This response leads to up-regulation of the Type III Secretion System, a key virulence factor. Unlike quorum sensing, which relies on diffusible chemical signals, pressorum sensing utilizes mechanical cues to gauge population density and spatial confinement. In bacterial colonies, this mechanism generates striking spatial patterns of cAMP signaling, including traveling rings that coincide with step-like structures in colony morphology. Our findings reveal a previously unknown link between mechanical compression and bacterial virulence, providing new insights into how P. aeruginosa coordinates population-level responses in confined environments. This work also expands our knowledge of mechanogenetics and opens up new possibilities in synthetic biology and bioengineering applications.
细菌采用各种策略来协调种群行为，其中法定人数感应是一种行之有效的机制。在这里，我们报告了铜绿假单胞菌的一种新型种群级调控机制，我们称之为 "压力感应"。这种机制允许细菌在密闭空间中调节其集体行为，以应对生长诱导的机械压缩。我们将高灵敏度的 cAMP 生物传感器与微流控技术相结合，证明了当压缩力达到约 30 nN 时，铜绿假单胞菌细胞会通过 Pil-Chp 化学传感系统迅速提高细胞内的 cAMP 水平。这种反应会导致 III 型分泌系统（一种关键的毒力因子）的上调。法定人数感应依赖于可扩散的化学信号，与之不同的是，压力感应利用机械线索来衡量种群密度和空间限制。在细菌菌落中，这种机制会产生引人注目的 cAMP 信号空间模式，包括与菌落形态中的阶梯状结构相吻合的行进环。我们的研究结果揭示了机械压缩与细菌毒力之间以前未知的联系，为了解铜绿微囊藻如何在封闭环境中协调种群级反应提供了新的视角。这项工作还拓展了我们对机械遗传学的认识，为合成生物学和生物工程应用开辟了新的可能性。
{"title":"Pressorum Sensing: Growth-induced Compression Activates cAMP Signaling in Pseudomonas aeruginosa","authors":"Lei Ni, Yajia Huang, Yaoxin Huang, Yue Yu, Jiarui Xiong, Hui Wen, Wenwen Xiao, Haiyi Liang, Fan Jin","doi":"10.1101/2024.07.08.602437","DOIUrl":"https://doi.org/10.1101/2024.07.08.602437","url":null,"abstract":"Bacteria employ various strategies to coordinate population-level behaviors, with quorum sensing being a well-established mechanism. Here, we report a novel population-level regulatory mechanism in Pseudomonas aeruginosa, which we term ‘pressorum sensing’. This mechanism allows bacteria to modulate their collective behavior in response to growth-induced mechanical compression in confined spaces. Using a highly sensitive cAMP biosensor in combination with microfluidics, we demonstrate that when compressive forces reach approximately 30 nN, P. aeruginosa cells rapidly increases intracellular cAMP levels via the Pil-Chp chemosensory system. This response leads to up-regulation of the Type III Secretion System, a key virulence factor. Unlike quorum sensing, which relies on diffusible chemical signals, pressorum sensing utilizes mechanical cues to gauge population density and spatial confinement. In bacterial colonies, this mechanism generates striking spatial patterns of cAMP signaling, including traveling rings that coincide with step-like structures in colony morphology. Our findings reveal a previously unknown link between mechanical compression and bacterial virulence, providing new insights into how P. aeruginosa coordinates population-level responses in confined environments. This work also expands our knowledge of mechanogenetics and opens up new possibilities in synthetic biology and bioengineering applications.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141640391","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 : 2024-07-16DOI: 10.1101/2024.07.10.602971
Brigit High, Thomas E. Finger
Taste buds are commonly studied in rodent models, but some differences exist between mice and humans in terms of gustatory mechanisms and sensitivities. Whether these functional differences are reflected in structural differences between species is unclear. Using immunofluorescent image stacks, we compared morphological and molecular characteristics of mouse and human fungiform taste buds. The results suggest that while the general features of fungiform taste buds are similar between mice and humans, several characteristics differ significantly. Human taste buds are larger and taller than those of mice, yet they contain similar numbers of taste cells. Taste buds in humans are more heavily innervated by gustatory nerve fibers expressing the purinergic receptor P2X3 showing a 40% higher innervation density than in mice. Like Type II cells of mice, a subset (about 30%) of cells in human taste buds is immunoreactive for PLCβ2. These PLCβ2-immunoreactive cells display CALHM1-immunoreactive puncta closely apposed to gustatory nerve fibers suggestive of channel-type synapses described in mice. These puncta, used as a measure of synaptic contact, are however significantly larger in humans compared to mice. Altogether these findings suggest that while many similarities exist in the structural organization of murine and human fungiform taste buds, significant differences do exist in taste bud size, innervation density, and size of synaptic contacts that may impact gustatory signal transmission.
{"title":"Structural comparisons of human and mouse fungiform taste buds","authors":"Brigit High, Thomas E. Finger","doi":"10.1101/2024.07.10.602971","DOIUrl":"https://doi.org/10.1101/2024.07.10.602971","url":null,"abstract":"Taste buds are commonly studied in rodent models, but some differences exist between mice and humans in terms of gustatory mechanisms and sensitivities. Whether these functional differences are reflected in structural differences between species is unclear. Using immunofluorescent image stacks, we compared morphological and molecular characteristics of mouse and human fungiform taste buds. The results suggest that while the general features of fungiform taste buds are similar between mice and humans, several characteristics differ significantly. Human taste buds are larger and taller than those of mice, yet they contain similar numbers of taste cells. Taste buds in humans are more heavily innervated by gustatory nerve fibers expressing the purinergic receptor P2X3 showing a 40% higher innervation density than in mice. Like Type II cells of mice, a subset (about 30%) of cells in human taste buds is immunoreactive for PLCβ2. These PLCβ2-immunoreactive cells display CALHM1-immunoreactive puncta closely apposed to gustatory nerve fibers suggestive of channel-type synapses described in mice. These puncta, used as a measure of synaptic contact, are however significantly larger in humans compared to mice. Altogether these findings suggest that while many similarities exist in the structural organization of murine and human fungiform taste buds, significant differences do exist in taste bud size, innervation density, and size of synaptic contacts that may impact gustatory signal transmission.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641880","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 : 2024-07-16DOI: 10.1101/2024.07.10.603006
Samuel Boscq, I. Theodorou, Roman Milstein, Aude Le Bail, Sabine Chenivesse, Bernard Billoud, Bénédicte Charrier
The initiation of embryogenesis in the kelp Saccharina latissima is accompanied by significant anisotropy in cell shape. Using monoclonal antibodies, we show that this anisotropy coincides with a spatio-temporal pattern of accumulation of alginates in the cell wall of the zygote and embryo. Alginates rich in guluronates as well as sulphated fucans show a homogeneous distribution in the embryo throughout Phase I of embryogenesis, but mannuronate alginates accumulate mainly on the sides of the zygote and embryo, disappearing as the embryo enlarges at the start of Phase II. This pattern depends on the presence of cortical actin filaments. In contrast, within the embryo lamina, the alginate composition of the walls newly formed by cytokinesis is not affected by the depolymerisation of actin filaments. Thus, in addition to revealing the existence of a mannuronate-rich alginate corset that may restrict the enlargement of the zygote and the embryo, thereby promoting the formation of the apico-basal growth axis, we demonstrate stage- and cytoskeleton-dependent differences in cell wall deposition in Saccharina embryos.
{"title":"The longitudinal growth of the embryo of the kelp Saccharina depends on actin filaments that control the formation of an alginate corset in the cell wall","authors":"Samuel Boscq, I. Theodorou, Roman Milstein, Aude Le Bail, Sabine Chenivesse, Bernard Billoud, Bénédicte Charrier","doi":"10.1101/2024.07.10.603006","DOIUrl":"https://doi.org/10.1101/2024.07.10.603006","url":null,"abstract":"The initiation of embryogenesis in the kelp Saccharina latissima is accompanied by significant anisotropy in cell shape. Using monoclonal antibodies, we show that this anisotropy coincides with a spatio-temporal pattern of accumulation of alginates in the cell wall of the zygote and embryo. Alginates rich in guluronates as well as sulphated fucans show a homogeneous distribution in the embryo throughout Phase I of embryogenesis, but mannuronate alginates accumulate mainly on the sides of the zygote and embryo, disappearing as the embryo enlarges at the start of Phase II. This pattern depends on the presence of cortical actin filaments. In contrast, within the embryo lamina, the alginate composition of the walls newly formed by cytokinesis is not affected by the depolymerisation of actin filaments. Thus, in addition to revealing the existence of a mannuronate-rich alginate corset that may restrict the enlargement of the zygote and the embryo, thereby promoting the formation of the apico-basal growth axis, we demonstrate stage- and cytoskeleton-dependent differences in cell wall deposition in Saccharina embryos.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642031","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 : 2024-07-16DOI: 10.1101/2024.07.13.603368
C. Pauli, M. Kienhöfer, M. Blank, Oguzhan Begik, Christian Rohde, D. Heid, Fu Xu, Sarah Miriam Naomi Zimmermann, Katharina Weidenauer, Sylvain Delaunay, Nadja Krall, Katrin Trunk, Duoduo Zhao, Fengbiao Zhou, Anke Heit-Mondrzyk, U. Platzbecker, Claudia Baldus, H. Serve, M. Bornhäuser, Cathrine Broberg Vågbø, Salvador Aznar Benitah, Jeroen Krijgsveld, E. Novoa, Carsten Müller-Tidow, Michaela Frye
RNA modification pathways are mis-regulated in multiple types of human cancer. To comprehensively identify cancer-relevant RNA modifications and their regulators, we screened all 150 annotated human RNA modifying proteins across 18 different normal and cancer cell lines using a CRISPR-based genetic knockout system. Fifty RNA modifying proteins were essential for survival of at least one cell type. A third of these essential genes were amplified in 38 different human primary cancer types and potentially drive cancer growth. Unexpectedly, the number of essential genes per cell line varied considerably, and this variation was not due to tissue of origin. Instead, we found that cancer cell-specific mitochondrial metabolic plasticity was responsible for the unique requirement of certain RNA modifications. For example, leukemia cells with high intrinsic drug tolerance required mitochondrial flexibility to survive treatment with the anti-leukemic drugs cytarabine and venetoclax. Synthetic lethality screens revealed that drug-resistance is abolished by deleting the mitochondrial methyltransferase TRMT5, which is responsible for the formation of N1-methylguanosine (m1G) in the tRNA anticodon loop. In summary, our study identifies cancer-relevant RNA modifying enzymes, and reveals a novel promising drug target for therapy-resistant acute myeloid leukemia.
{"title":"Unbiased functional genetic screens reveal essential RNA modifications in human cancer and drug resistance","authors":"C. Pauli, M. Kienhöfer, M. Blank, Oguzhan Begik, Christian Rohde, D. Heid, Fu Xu, Sarah Miriam Naomi Zimmermann, Katharina Weidenauer, Sylvain Delaunay, Nadja Krall, Katrin Trunk, Duoduo Zhao, Fengbiao Zhou, Anke Heit-Mondrzyk, U. Platzbecker, Claudia Baldus, H. Serve, M. Bornhäuser, Cathrine Broberg Vågbø, Salvador Aznar Benitah, Jeroen Krijgsveld, E. Novoa, Carsten Müller-Tidow, Michaela Frye","doi":"10.1101/2024.07.13.603368","DOIUrl":"https://doi.org/10.1101/2024.07.13.603368","url":null,"abstract":"RNA modification pathways are mis-regulated in multiple types of human cancer. To comprehensively identify cancer-relevant RNA modifications and their regulators, we screened all 150 annotated human RNA modifying proteins across 18 different normal and cancer cell lines using a CRISPR-based genetic knockout system. Fifty RNA modifying proteins were essential for survival of at least one cell type. A third of these essential genes were amplified in 38 different human primary cancer types and potentially drive cancer growth. Unexpectedly, the number of essential genes per cell line varied considerably, and this variation was not due to tissue of origin. Instead, we found that cancer cell-specific mitochondrial metabolic plasticity was responsible for the unique requirement of certain RNA modifications. For example, leukemia cells with high intrinsic drug tolerance required mitochondrial flexibility to survive treatment with the anti-leukemic drugs cytarabine and venetoclax. Synthetic lethality screens revealed that drug-resistance is abolished by deleting the mitochondrial methyltransferase TRMT5, which is responsible for the formation of N1-methylguanosine (m1G) in the tRNA anticodon loop. In summary, our study identifies cancer-relevant RNA modifying enzymes, and reveals a novel promising drug target for therapy-resistant acute myeloid leukemia.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642083","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 : 2024-07-16DOI: 10.1101/2024.07.11.603165
Ahmed Khattab, Shang-Fu Chen, Nathan Wineinger, Ali Torkamani
Background The All of Us (AoU) Research Program provides a comprehensive genomic dataset to accelerate health research and medical breakthroughs. Despite its potential, researchers face significant challenges, including high costs and inefficiencies associated with data extraction and analysis. AoUPRS addresses these challenges by offering a versatile and cost-effective tool for calculating polygenic risk scores (PRS), enabling both experienced and novice researchers to leverage the AoU dataset for significant genomic discoveries. Results AoUPRS is implemented in Python and utilizes the Hail framework for genomic data analysis. It offers two distinct approaches for PRS calculation: the Hail MatrixTable (MT) and the Hail Variant Dataset (VDS). The MT approach provides a dense representation of genotype data, while the VDS approach offers a sparse representation, significantly reducing computational costs. In performance evaluations, the VDS approach demonstrated a cost reduction of up to 99.51% for smaller scores and 85% for larger scores compared to the MT approach. Both approaches yielded similar predictive power, as shown by logistic regression analyses of PRS for coronary artery disease, atrial fibrillation, and type 2 diabetes. The empirical cumulative distribution functions (ECDFs) for PRS values further confirmed the consistency between the two methods. Conclusions AoUPRS is a versatile and cost-effective tool that addresses the high costs and inefficiencies associated with PRS calculations using the AoU dataset. By offering both dense and sparse data processing approaches, AoUPRS allows researchers to choose the approach best suited to their needs, facilitating genomic discoveries. The tool’s open-source availability on GitHub, coupled with detailed documentation and tutorials, ensures accessibility and ease of use for the scientific community.
{"title":"AoUPRS: A Cost-Effective and Versatile PRS Calculator for the All of Us Program","authors":"Ahmed Khattab, Shang-Fu Chen, Nathan Wineinger, Ali Torkamani","doi":"10.1101/2024.07.11.603165","DOIUrl":"https://doi.org/10.1101/2024.07.11.603165","url":null,"abstract":"Background The All of Us (AoU) Research Program provides a comprehensive genomic dataset to accelerate health research and medical breakthroughs. Despite its potential, researchers face significant challenges, including high costs and inefficiencies associated with data extraction and analysis. AoUPRS addresses these challenges by offering a versatile and cost-effective tool for calculating polygenic risk scores (PRS), enabling both experienced and novice researchers to leverage the AoU dataset for significant genomic discoveries. Results AoUPRS is implemented in Python and utilizes the Hail framework for genomic data analysis. It offers two distinct approaches for PRS calculation: the Hail MatrixTable (MT) and the Hail Variant Dataset (VDS). The MT approach provides a dense representation of genotype data, while the VDS approach offers a sparse representation, significantly reducing computational costs. In performance evaluations, the VDS approach demonstrated a cost reduction of up to 99.51% for smaller scores and 85% for larger scores compared to the MT approach. Both approaches yielded similar predictive power, as shown by logistic regression analyses of PRS for coronary artery disease, atrial fibrillation, and type 2 diabetes. The empirical cumulative distribution functions (ECDFs) for PRS values further confirmed the consistency between the two methods. Conclusions AoUPRS is a versatile and cost-effective tool that addresses the high costs and inefficiencies associated with PRS calculations using the AoU dataset. By offering both dense and sparse data processing approaches, AoUPRS allows researchers to choose the approach best suited to their needs, facilitating genomic discoveries. The tool’s open-source availability on GitHub, coupled with detailed documentation and tutorials, ensures accessibility and ease of use for the scientific community.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642104","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 : 2024-07-16DOI: 10.1101/2024.07.11.603078
Lane M. Atmore, Inge van der Jagt, Aurélie Boilard, Simone Häberle, Rachel Blevis, Katrien Dierickx, Liz M. Quinlan, David Orton, A. Hufthammer, J. H. Barrett, Bastiaan Star
Atlantic herring populations have been the target of highly profitable coastal and pelagic fisheries in northern Europe for well over a thousand years. Their complex and intermingled population dynamics have sparked extensive debate over the impacts of historical overfishing and have complicated their sustainable management today. Recently developed tools – including diagnostic SNP panels for mixed-stock analysis – aim to improve population assignment for fisheries management, however, the biological relevance of such tools over long periods of time remains unknown. Here, we demonstrate the millennium-long applicability of diagnostic SNP panels and identify population perturbations associated with increasing exploitation pressure and climate change by analyzing whole genome data from modern and ancient herring specimens. We find that herring demographic cycles were likely within healthy ecosystem boundaries until the dramatic disruption of these cycles in the 20th century. We find only autumn-spawning herring in our archaeological remains spanning 900 years from 8 sites across Europe, supporting observations that the numerical dominance of specific spawning populations can demographically outcompete other herring types. We also obtain pre-archival aDNA evidence for the famous, cyclical “Bohuslän periods,” during which mass quantities of North Sea autumn-spawning herring congregated in the Skagerrak. Finally, the long-term applicability of diagnostic SNP panels underscores their highly cost-effective application for the genetic monitoring of herring stocks. Our results highlight the utility of ancient DNA and genomic analysis to obtain historical and natural insights in herring ecology and population dynamics with relevance for sustainable fisheries management.
一千多年来，大西洋鲱鱼种群一直是北欧沿海和远洋渔业的高利润目标。其复杂而交错的种群动态引发了有关历史上过度捕捞影响的广泛讨论，并使其如今的可持续管理变得复杂。最近开发的工具--包括用于混合种群分析的诊断性 SNP 面板--旨在改进用于渔业管理的种群分配，然而，这些工具在很长一段时间内的生物学相关性仍然未知。在这里，我们通过分析现代和古代鲱鱼标本的全基因组数据，证明了诊断性 SNP 面板的千年适用性，并确定了与日益增长的开发压力和气候变化相关的种群扰动。我们发现，鲱鱼的种群周期很可能一直处于健康的生态系统边界内，直到 20 世纪这些周期被严重破坏。我们在欧洲 8 个遗址的考古遗存中发现，900 年来只有秋季产卵的鲱鱼，这支持了特定产卵种群的数量优势可以在人口统计学上超越其他类型鲱鱼的观点。我们还获得了著名的周期性 "Bohuslän 期 "的考古前 aDNA 证据，在此期间，大量北海秋季产卵的鲱鱼聚集在斯卡格拉克海峡。最后，诊断性 SNP 面板的长期适用性凸显了其在鲱鱼种群遗传监测方面极具成本效益的应用。我们的研究结果凸显了古 DNA 和基因组分析在鲱鱼生态学和种群动态方面的历史和自然洞察力，对可持续渔业管理具有重要意义。
{"title":"The Once and Future Fish: 1300 years of Atlantic herring population structure and demography revealed through ancient DNA and mixed-stock analysis","authors":"Lane M. Atmore, Inge van der Jagt, Aurélie Boilard, Simone Häberle, Rachel Blevis, Katrien Dierickx, Liz M. Quinlan, David Orton, A. Hufthammer, J. H. Barrett, Bastiaan Star","doi":"10.1101/2024.07.11.603078","DOIUrl":"https://doi.org/10.1101/2024.07.11.603078","url":null,"abstract":"Atlantic herring populations have been the target of highly profitable coastal and pelagic fisheries in northern Europe for well over a thousand years. Their complex and intermingled population dynamics have sparked extensive debate over the impacts of historical overfishing and have complicated their sustainable management today. Recently developed tools – including diagnostic SNP panels for mixed-stock analysis – aim to improve population assignment for fisheries management, however, the biological relevance of such tools over long periods of time remains unknown. Here, we demonstrate the millennium-long applicability of diagnostic SNP panels and identify population perturbations associated with increasing exploitation pressure and climate change by analyzing whole genome data from modern and ancient herring specimens. We find that herring demographic cycles were likely within healthy ecosystem boundaries until the dramatic disruption of these cycles in the 20th century. We find only autumn-spawning herring in our archaeological remains spanning 900 years from 8 sites across Europe, supporting observations that the numerical dominance of specific spawning populations can demographically outcompete other herring types. We also obtain pre-archival aDNA evidence for the famous, cyclical “Bohuslän periods,” during which mass quantities of North Sea autumn-spawning herring congregated in the Skagerrak. Finally, the long-term applicability of diagnostic SNP panels underscores their highly cost-effective application for the genetic monitoring of herring stocks. Our results highlight the utility of ancient DNA and genomic analysis to obtain historical and natural insights in herring ecology and population dynamics with relevance for sustainable fisheries management.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141640266","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 : 2024-07-16DOI: 10.1101/2024.07.12.603245
Kurt Gemeinhardt, Byoung Seung Jeon, J. Ntihuga, Han Wang, Caroline Schlaiß, Timo N. Lucas, I. Bessarab, Nicolas Nalpas, Nanqing Zhou, J. Usack, Daniel H. Huson, Rohan B. H. Williams, Boris Maček, Ludmilla Aristilde, L. T. Angenent
Previous bioreactor studies achieved high volumetric n-caprylate (i.e., n-octanoate) production rates and selectivities from ethanol and acetate with chain-elongating microbiomes. However, the metabolic pathways from the substrates to n-caprylate synthesis were unclear. We operated two n-caprylate-producing upflow bioreactors with a synthetic medium to study the underlying metabolic pathways. The operating period exceeded 2.5 years, with a peak volumetric n-caprylate production rate of 190 ± 8.4 mmol C L-1 d-1 (0.14 g L-1 h-1). We identified oxygen availability as a critical performance parameter, facilitating intermediate metabolite production from ethanol. Bottle experiments in the presence and absence of oxygen with 13C-labeled ethanol suggest acetyl-coenzyme A-based derived production of n-butyrate (i.e., n-butanoate), n-caproate (i.e., n-hexanoate), and n-caprylate. Here, we postulate a trophic hierarchy within the bioreactor microbiomes based on metagenomics, metaproteomics, and metabolomics data, as well as experiments with a Clostridium kluyveri isolate. First, the aerobic bacterium Pseudoclavibacter caeni and the facultative anaerobic fungus Cyberlindnera jadinii converted part of the ethanol pool into the intermediate metabolites succinate, lactate, and pyroglutamate. Second, the strict anaerobic C. kluyveri elongated acetate with the residual ethanol to n-butyrate. Third, Caproicibacter fermentans and Oscillibacter valericigenes elongated n-butyrate with the intermediate metabolites to n-caproate and then to n-caprylate. Among the carbon chain-elongating pathways of carboxylates, the tricarboxylic acid cycle and the reverse ß-oxidation pathways showed a positive correlation with n-caprylate production. The results of this study inspire the realization of a chain-elongating production platform with separately controlled aerobic and anaerobic stages to produce n-caprylate renewably as an attractive chemical from ethanol and acetate as substrates. Broader context Next to renewable electric energy, carbon-based chemicals have to be produced sustainably and independently from fossil sources. To meet this goal, we must expand the portfolio of bio-based conversion technologies on an industrial scale to cover as many target chemicals as possible. We explore the bioprocess of chain elongation to provide medium-chain carboxylates that can function as future platform chemicals in the circular economy. The most valuable medium-chain carboxylate produced with chain elongation is n-caprylate (i.e., n-octanoate). This molecule with eight carbon atoms in a row (C8) is challenging to produce renewably for the chemical industry. Previous reports elucidated that elevated ethanol-to-acetate ratios, which are found in syngas-fermentation effluent, stimulated n-caprylate production. Until now, studies have suggested that chain elongation from high concentrations of ethanol and acetate is a fully anaerobic process. We refine this view by showing a trophic hi
之前的生物反应器研究利用链延伸微生物群从乙醇和乙酸酯中获得了较高的正辛酸酯（即正辛酸）生产率和选择性。然而，从底物到正辛酸酯合成的代谢途径尚不清楚。我们使用合成培养基运行了两个生产正辛酸酯的上流式生物反应器，以研究基本代谢途径。运行时间超过 2.5 年，正辛酸酯的峰值体积生产率为 190 ± 8.4 mmol C L-1 d-1 （0.14 g L-1 h-1）。我们发现氧气供应是一个关键的性能参数，有利于乙醇中间代谢产物的生产。用 13C 标记的乙醇在有氧和无氧条件下进行的瓶内实验表明，乙酰辅酶 A 可产生正丁酸盐（即正丁酸盐）、正己酸盐（即正己酸盐）和正辛酸盐。在此，我们根据元基因组学、元蛋白组学和代谢组学数据，以及 kluyveri梭菌分离物的实验，推测了生物反应器微生物组内的营养层次结构。首先，好氧菌 Pseudoclavibacter caeni 和兼性厌氧真菌 Cyberlindnera jadinii 将部分乙醇池转化为中间代谢产物琥珀酸、乳酸和焦谷氨酸。其次，严格厌氧的 C. kluyveri 将乙酸与残余乙醇拉长为正丁酸。第三，Caproicibacter fermentans 和 Oscillibacter valericigenes 将正丁酸与中间代谢物一起延长为正己酸，然后再延长为正辛酸。在羧酸盐的碳链延长途径中，三羧酸循环和反ß-氧化途径与正辛酸酯的生成呈正相关。这项研究的结果启发人们建立一个链延伸生产平台，分别控制好氧和厌氧阶段，以乙醇和乙酸酯为底物，可再生地生产正辛酸酯这种有吸引力的化学品。更广泛的背景 除了可再生电力能源之外，碳基化学品的生产也必须以可持续的方式独立于化石资源。为了实现这一目标，我们必须扩大工业规模的生物基转化技术组合，以涵盖尽可能多的目标化学品。我们探索了生物链拉长过程，以提供可作为未来循环经济平台化学品的中链羧酸盐。利用链延长法生产的最有价值的中链羧酸盐是正辛酸酯（即正辛酸）。这种分子中一排有八个碳原子（C8），对于化学工业来说，以可再生方式生产具有挑战性。以前的报告阐明，合成气发酵废水中乙醇与乙酸的比率升高会刺激正辛酸酯的生产。到目前为止，研究一直认为高浓度乙醇和乙酸酯的链延伸是一个完全厌氧的过程。我们通过展示能够促进这一过程的需氧和厌氧微生物的营养层次，完善了这一观点。适当的氧气补充可使琥珀酸、乳酸和焦谷氨酸得以合成，从而允许在厌氧条件下高速链延长至正辛酸。鉴于这些结果，未来的研究应侧重于好氧和厌氧微生物的分离研究，以进一步提高工艺性能，从而在工业规模上可再生地生产正辛酸酯。
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Pub Date : 2024-07-16DOI: 10.1101/2024.07.11.602993
Nathalie Khoury, Michelle E Pizzo, Claire B Discenza, David Joy, David Tatarakis, Mihail I. Todorov, Moritz Negwer, Connie Ha, G. L. de Melo, Lily Sarrafha, Matthew J. Simon, Darren Chan, Roni Chau, Kylie S Chew, Johann Chow, Allisa Clemens, Yaneth Robles-Colmenares, Jason C Dugas, Joseph Duque, Doris Kaltenecker, Holly Kane, A. Leung, Edwin I Lozano, Arash Moshkforoush, E. Roche, T. Sandmann, Mabel Tong, Kaitlin Xa, Yinhan Zhou, Joseph W. Lewcock, Ali Ertürk, Robert G Thorne, Meredith E K Calvert, Y. J. Y. Zuchero
The blood-brain barrier (BBB) poses a significant challenge drug delivery to the brain. BBB-crossing molecules are emerging as a new class of therapeutics with significant potential for central nervous system (CNS) indications. In particular, transferrin receptor (TfR)- and CD98 heavy chain (CD98hc)-targeting molecules have been demonstrated to cross the BBB for enhanced brain delivery. Previously, we reported TfR and CD98hc antibody transport vehicles (ATVTfR and ATVCD98hc) that utilize these BBB receptors to improve CNS drug delivery1,2. Here, we provide a comprehensive and unbiased biodistribution characterization of ATVTfR and ATVCD98hc compared to a standard IgG at a multiscale level, ranging from whole-body to brain region- and cell type-targeting specificity. Mouse whole-body tissue clearing revealed distinct organ localization for each molecule. In the CNS, ATVTfR and ATVCD98hc not only achieves enhanced brain delivery but importantly, much broader parenchymal distribution in contrast to the severely limited distribution observed with a standard antibody that was not able to be improved even at very high dose levels. Using cell sorting and single-cell RNA sequencing of mouse brain, we revealed that standard IgG predominantly localizes to perivascular and leptomeningeal cells and reaches the CNS by entering the CSF, rather than crossing the BBB. In contrast, ATVTfR and ATVCD98hc enables broad parenchymal cell-specific distribution via transcytosis through brain endothelial cells (BECs) along the neurovasculature. Finally, we extended the translational relevance of our findings by revealing enhanced and broad brain and spinal cord biodistribution of ATVTfR compared to standard IgG in cynomolgus monkey. Taken together, this multiscale analysis reveals in-depth biodistribution differences between ATVTfR, ATVCD98hc, and standard IgG. These results may better inform platform selection for specific therapeutic targets of interest, optimally matching platforms to desired CNS target engagement, peripheral organ exposures, and predict or potentially reduce off-target effects.
{"title":"Fc-engineered large molecules targeting blood-brain barrier transferrin receptor and CD98hc have distinct central nervous system and peripheral biodistribution compared to standard antibodies","authors":"Nathalie Khoury, Michelle E Pizzo, Claire B Discenza, David Joy, David Tatarakis, Mihail I. Todorov, Moritz Negwer, Connie Ha, G. L. de Melo, Lily Sarrafha, Matthew J. Simon, Darren Chan, Roni Chau, Kylie S Chew, Johann Chow, Allisa Clemens, Yaneth Robles-Colmenares, Jason C Dugas, Joseph Duque, Doris Kaltenecker, Holly Kane, A. Leung, Edwin I Lozano, Arash Moshkforoush, E. Roche, T. Sandmann, Mabel Tong, Kaitlin Xa, Yinhan Zhou, Joseph W. Lewcock, Ali Ertürk, Robert G Thorne, Meredith E K Calvert, Y. J. Y. Zuchero","doi":"10.1101/2024.07.11.602993","DOIUrl":"https://doi.org/10.1101/2024.07.11.602993","url":null,"abstract":"The blood-brain barrier (BBB) poses a significant challenge drug delivery to the brain. BBB-crossing molecules are emerging as a new class of therapeutics with significant potential for central nervous system (CNS) indications. In particular, transferrin receptor (TfR)- and CD98 heavy chain (CD98hc)-targeting molecules have been demonstrated to cross the BBB for enhanced brain delivery. Previously, we reported TfR and CD98hc antibody transport vehicles (ATVTfR and ATVCD98hc) that utilize these BBB receptors to improve CNS drug delivery1,2. Here, we provide a comprehensive and unbiased biodistribution characterization of ATVTfR and ATVCD98hc compared to a standard IgG at a multiscale level, ranging from whole-body to brain region- and cell type-targeting specificity. Mouse whole-body tissue clearing revealed distinct organ localization for each molecule. In the CNS, ATVTfR and ATVCD98hc not only achieves enhanced brain delivery but importantly, much broader parenchymal distribution in contrast to the severely limited distribution observed with a standard antibody that was not able to be improved even at very high dose levels. Using cell sorting and single-cell RNA sequencing of mouse brain, we revealed that standard IgG predominantly localizes to perivascular and leptomeningeal cells and reaches the CNS by entering the CSF, rather than crossing the BBB. In contrast, ATVTfR and ATVCD98hc enables broad parenchymal cell-specific distribution via transcytosis through brain endothelial cells (BECs) along the neurovasculature. Finally, we extended the translational relevance of our findings by revealing enhanced and broad brain and spinal cord biodistribution of ATVTfR compared to standard IgG in cynomolgus monkey. Taken together, this multiscale analysis reveals in-depth biodistribution differences between ATVTfR, ATVCD98hc, and standard IgG. These results may better inform platform selection for specific therapeutic targets of interest, optimally matching platforms to desired CNS target engagement, peripheral organ exposures, and predict or potentially reduce off-target effects.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141643286","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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