Pub Date : 2021-03-03DOI: 10.5194/EGUSPHERE-EGU21-5731
N. Leach, A. Weisheimer, M. Allen, T. Palmer
Significance The question of how humans have influenced individual extreme weather events is both scientifically and socially important. However, deficiencies in climate models’ representations of key mechanisms within the process chains that drive weather reduce our confidence in estimates of the human influence on extreme events. We propose that using forecast models that successfully predicted the event in question could increase the robustness of such estimates. Using a successful forecast means we can be confident that the model is able to faithfully represent the characteristics of the specific extreme event. We use this forecast-based methodology to estimate the direct radiative impact of increased CO2 concentrations (one component, but not the entirety, of human influence) on the European heatwave of February 2019. Attribution of extreme weather events has expanded rapidly as a field over the past decade. However, deficiencies in climate model representation of key dynamical drivers of extreme events have led to some concerns over the robustness of climate model–based attribution studies. It has also been suggested that the unconditioned risk-based approach to event attribution may result in false negative results due to dynamical noise overwhelming any climate change signal. The “storyline” attribution framework, in which the impact of climate change on individual drivers of an extreme event is examined, aims to mitigate these concerns. Here we propose a methodology for attribution of extreme weather events using the operational European Centre for Medium-Range Weather Forecasts (ECMWF) medium-range forecast model that successfully predicted the event. The use of a successful forecast ensures not only that the model is able to accurately represent the event in question, but also that the analysis is unequivocally an attribution of this specific event, rather than a mixture of multiple different events that share some characteristic. Since this attribution methodology is conditioned on the component of the event that was predictable at forecast initialization, we show how adjusting the lead time of the forecast can flexibly set the level of conditioning desired. This flexible adjustment of the conditioning allows us to synthesize between a storyline (highly conditioned) and a risk-based (relatively unconditioned) approach. We demonstrate this forecast-based methodology through a partial attribution of the direct radiative effect of increased CO2 concentrations on the exceptional European winter heatwave of February 2019.
{"title":"Forecast-based attribution of a winter heatwave within the limit of predictability","authors":"N. Leach, A. Weisheimer, M. Allen, T. Palmer","doi":"10.5194/EGUSPHERE-EGU21-5731","DOIUrl":"https://doi.org/10.5194/EGUSPHERE-EGU21-5731","url":null,"abstract":"Significance The question of how humans have influenced individual extreme weather events is both scientifically and socially important. However, deficiencies in climate models’ representations of key mechanisms within the process chains that drive weather reduce our confidence in estimates of the human influence on extreme events. We propose that using forecast models that successfully predicted the event in question could increase the robustness of such estimates. Using a successful forecast means we can be confident that the model is able to faithfully represent the characteristics of the specific extreme event. We use this forecast-based methodology to estimate the direct radiative impact of increased CO2 concentrations (one component, but not the entirety, of human influence) on the European heatwave of February 2019. Attribution of extreme weather events has expanded rapidly as a field over the past decade. However, deficiencies in climate model representation of key dynamical drivers of extreme events have led to some concerns over the robustness of climate model–based attribution studies. It has also been suggested that the unconditioned risk-based approach to event attribution may result in false negative results due to dynamical noise overwhelming any climate change signal. The “storyline” attribution framework, in which the impact of climate change on individual drivers of an extreme event is examined, aims to mitigate these concerns. Here we propose a methodology for attribution of extreme weather events using the operational European Centre for Medium-Range Weather Forecasts (ECMWF) medium-range forecast model that successfully predicted the event. The use of a successful forecast ensures not only that the model is able to accurately represent the event in question, but also that the analysis is unequivocally an attribution of this specific event, rather than a mixture of multiple different events that share some characteristic. Since this attribution methodology is conditioned on the component of the event that was predictable at forecast initialization, we show how adjusting the lead time of the forecast can flexibly set the level of conditioning desired. This flexible adjustment of the conditioning allows us to synthesize between a storyline (highly conditioned) and a risk-based (relatively unconditioned) approach. We demonstrate this forecast-based methodology through a partial attribution of the direct radiative effect of increased CO2 concentrations on the exceptional European winter heatwave of February 2019.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"114 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77177586","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 : 2021-03-03DOI: 10.5194/egusphere-egu21-9227
M. Marani, G. Katul, W. Pan, A. Parolari
Significance Estimates of the probability of occurrence of intense epidemics based on the long-observed history of infectious diseases remain lagging or lacking altogether. Here, we assemble and analyze a global dataset of large epidemics spanning four centuries. The rate of occurrence of epidemics varies widely in time, but the probability distribution of epidemic intensity assumes a constant form with a slowly decaying algebraic tail, implying that the probability of extreme epidemics decreases slowly with epidemic intensity. Together with recent estimates of increasing rates of disease emergence from animal reservoirs associated with environmental change, this finding suggests a high probability of observing pandemics similar to COVID-19 (probability of experiencing it in one’s lifetime currently about 38%), which may double in coming decades. Observational knowledge of the epidemic intensity, defined as the number of deaths divided by global population and epidemic duration, and of the rate of emergence of infectious disease outbreaks is necessary to test theory and models and to inform public health risk assessment by quantifying the probability of extreme pandemics such as COVID-19. Despite its significance, assembling and analyzing a comprehensive global historical record spanning a variety of diseases remains an unexplored task. A global dataset of historical epidemics from 1600 to present is here compiled and examined using novel statistical methods to estimate the yearly probability of occurrence of extreme epidemics. Historical observations covering four orders of magnitude of epidemic intensity follow a common probability distribution with a slowly decaying power-law tail (generalized Pareto distribution, asymptotic exponent = −0.71). The yearly number of epidemics varies ninefold and shows systematic trends. Yearly occurrence probabilities of extreme epidemics, Py, vary widely: Py of an event with the intensity of the “Spanish influenza” (1918 to 1920) varies between 0.27 and 1.9% from 1600 to present, while its mean recurrence time today is 400 y (95% CI: 332 to 489 y). The slow decay of probability with epidemic intensity implies that extreme epidemics are relatively likely, a property previously undetected due to short observational records and stationary analysis methods. Using recent estimates of the rate of increase in disease emergence from zoonotic reservoirs associated with environmental change, we estimate that the yearly probability of occurrence of extreme epidemics can increase up to threefold in the coming decades.
根据长期观察到的传染病历史，对发生强烈流行病的概率估计仍然滞后或完全缺乏。在这里，我们收集并分析了跨越四个世纪的大型流行病的全球数据集。流行病的发生率随时间变化很大，但流行病强度的概率分布呈常数形式，具有缓慢衰减的代数尾，这意味着极端流行病的概率随流行强度缓慢下降。再加上最近对与环境变化相关的动物宿主疾病发生率上升的估计，这一发现表明，观察到类似于COVID-19的大流行的可能性很高(目前在人的一生中经历它的可能性约为38%)，在未来几十年可能会翻一番。对流行病强度(定义为死亡人数除以全球人口和流行持续时间)和传染病暴发出现率的观察性了解，对于检验理论和模型，以及通过量化COVID-19等极端流行病的概率，为公共卫生风险评估提供信息是必要的。尽管具有重要意义，但收集和分析涵盖各种疾病的全面全球历史记录仍然是一项未开发的任务。本文编制了从1600年至今的历史流行病的全球数据集，并使用新的统计方法进行了检查，以估计每年发生极端流行病的概率。覆盖4个量级流行病强度的历史观测值遵循具有缓慢衰减幂律尾部的共同概率分布(广义帕累托分布，渐近指数= - 0.71)。每年流行病的数量变化了九倍，并显示出系统的趋势。极端流行病的年发生概率Py变化很大:从1600年到现在，“西班牙流感”(1918年至1920年)强度的事件Py变化在0.27至1.9%之间，而其今天的平均复发时间为400 y (95% CI: 332至489 y)。概率随流行强度的缓慢衰减意味着极端流行病是相对可能的，由于观测记录短和平稳分析方法，这一特性以前未被发现。根据最近对与环境变化有关的人畜共患病水库的疾病出现增长率的估计，我们估计，在未来几十年里，每年发生极端流行病的概率可能增加三倍。
{"title":"Intensity and frequency of extreme novel epidemics","authors":"M. Marani, G. Katul, W. Pan, A. Parolari","doi":"10.5194/egusphere-egu21-9227","DOIUrl":"https://doi.org/10.5194/egusphere-egu21-9227","url":null,"abstract":"Significance Estimates of the probability of occurrence of intense epidemics based on the long-observed history of infectious diseases remain lagging or lacking altogether. Here, we assemble and analyze a global dataset of large epidemics spanning four centuries. The rate of occurrence of epidemics varies widely in time, but the probability distribution of epidemic intensity assumes a constant form with a slowly decaying algebraic tail, implying that the probability of extreme epidemics decreases slowly with epidemic intensity. Together with recent estimates of increasing rates of disease emergence from animal reservoirs associated with environmental change, this finding suggests a high probability of observing pandemics similar to COVID-19 (probability of experiencing it in one’s lifetime currently about 38%), which may double in coming decades. Observational knowledge of the epidemic intensity, defined as the number of deaths divided by global population and epidemic duration, and of the rate of emergence of infectious disease outbreaks is necessary to test theory and models and to inform public health risk assessment by quantifying the probability of extreme pandemics such as COVID-19. Despite its significance, assembling and analyzing a comprehensive global historical record spanning a variety of diseases remains an unexplored task. A global dataset of historical epidemics from 1600 to present is here compiled and examined using novel statistical methods to estimate the yearly probability of occurrence of extreme epidemics. Historical observations covering four orders of magnitude of epidemic intensity follow a common probability distribution with a slowly decaying power-law tail (generalized Pareto distribution, asymptotic exponent = −0.71). The yearly number of epidemics varies ninefold and shows systematic trends. Yearly occurrence probabilities of extreme epidemics, Py, vary widely: Py of an event with the intensity of the “Spanish influenza” (1918 to 1920) varies between 0.27 and 1.9% from 1600 to present, while its mean recurrence time today is 400 y (95% CI: 332 to 489 y). The slow decay of probability with epidemic intensity implies that extreme epidemics are relatively likely, a property previously undetected due to short observational records and stationary analysis methods. Using recent estimates of the rate of increase in disease emergence from zoonotic reservoirs associated with environmental change, we estimate that the yearly probability of occurrence of extreme epidemics can increase up to threefold in the coming decades.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86657034","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 : 2021-03-01DOI: 10.26434/CHEMRXIV.14130101.V1
A. H. Bork, M. Rekhtina, E. Willinger, Pedro Castro-Fernández, J. Drnec, P. Abdala, C. Müller
Significance The grand challenge of reducing CO2 emissions requires the development of cost-effective CO2 sorbents. Based on the theoretically obtainable weight-normalized CO2 uptake, MgO-based materials promoted with molten salts are attractive sorbents when compared to amines or metal organic frameworks. However, there is very little understanding of the processes that occur at the atomic-to-micro scale during CO2 capture conditions, hampering the advancement of such sorbents. Combining X-ray and electron-based characterization techniques, we observe that MgCO3 crystals form via nucleation and growth at the interface between MgO and the molten salt and are oriented with respect to the MgO(100) surface. Hence, more-effective MgO-based sorbents will require maximizing the interfacial area and the number of nucleation sites at the interface. The addition of molten alkali metal salts drastically accelerates the kinetics of CO2 capture by MgO through the formation of MgCO3. However, the growth mechanism, the nature of MgCO3 formation, and the exact role of the molten alkali metal salts on the CO2 capture process remain elusive, holding back the development of more-effective MgO-based CO2 sorbents. Here, we unveil the growth mechanism of MgCO3 under practically relevant conditions using a well-defined, yet representative, model system that is a MgO(100) single crystal coated with NaNO3. The model system is interrogated by in situ X-ray reflectometry coupled with grazing incidence X-ray diffraction, scanning electron microscopy, and high-resolution transmission electron microscopy. When bare MgO(100) is exposed to a flow of CO2, a noncrystalline surface carbonate layer of ca. 7-Å thickness forms. In contrast, when MgO(100) is coated with NaNO3, MgCO3 crystals nucleate and grow. These crystals have a preferential orientation with respect to the MgO(100) substrate, and form at the interface between MgO(100) and the molten NaNO3. MgCO3 grows epitaxially with respect to MgO(100), and the lattice mismatch between MgCO3 and MgO is relaxed through lattice misfit dislocations. Pyramid-shaped pits on the surface of MgO, in proximity to and below the MgCO3 crystals, point to the etching of surface MgO, providing dissolved [Mg2+…O2–] ionic pairs for MgCO3 growth. Our studies highlight the importance of combining X-rays and electron microscopy techniques to provide atomic to micrometer scale insight into the changes occurring at complex interfaces under reactive conditions.
{"title":"Peering into buried interfaces with X-rays and electrons to unveil MgCO3 formation during CO2 capture in molten salt-promoted MgO","authors":"A. H. Bork, M. Rekhtina, E. Willinger, Pedro Castro-Fernández, J. Drnec, P. Abdala, C. Müller","doi":"10.26434/CHEMRXIV.14130101.V1","DOIUrl":"https://doi.org/10.26434/CHEMRXIV.14130101.V1","url":null,"abstract":"Significance The grand challenge of reducing CO2 emissions requires the development of cost-effective CO2 sorbents. Based on the theoretically obtainable weight-normalized CO2 uptake, MgO-based materials promoted with molten salts are attractive sorbents when compared to amines or metal organic frameworks. However, there is very little understanding of the processes that occur at the atomic-to-micro scale during CO2 capture conditions, hampering the advancement of such sorbents. Combining X-ray and electron-based characterization techniques, we observe that MgCO3 crystals form via nucleation and growth at the interface between MgO and the molten salt and are oriented with respect to the MgO(100) surface. Hence, more-effective MgO-based sorbents will require maximizing the interfacial area and the number of nucleation sites at the interface. The addition of molten alkali metal salts drastically accelerates the kinetics of CO2 capture by MgO through the formation of MgCO3. However, the growth mechanism, the nature of MgCO3 formation, and the exact role of the molten alkali metal salts on the CO2 capture process remain elusive, holding back the development of more-effective MgO-based CO2 sorbents. Here, we unveil the growth mechanism of MgCO3 under practically relevant conditions using a well-defined, yet representative, model system that is a MgO(100) single crystal coated with NaNO3. The model system is interrogated by in situ X-ray reflectometry coupled with grazing incidence X-ray diffraction, scanning electron microscopy, and high-resolution transmission electron microscopy. When bare MgO(100) is exposed to a flow of CO2, a noncrystalline surface carbonate layer of ca. 7-Å thickness forms. In contrast, when MgO(100) is coated with NaNO3, MgCO3 crystals nucleate and grow. These crystals have a preferential orientation with respect to the MgO(100) substrate, and form at the interface between MgO(100) and the molten NaNO3. MgCO3 grows epitaxially with respect to MgO(100), and the lattice mismatch between MgCO3 and MgO is relaxed through lattice misfit dislocations. Pyramid-shaped pits on the surface of MgO, in proximity to and below the MgCO3 crystals, point to the etching of surface MgO, providing dissolved [Mg2+…O2–] ionic pairs for MgCO3 growth. Our studies highlight the importance of combining X-rays and electron microscopy techniques to provide atomic to micrometer scale insight into the changes occurring at complex interfaces under reactive conditions.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82018190","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 : 2021-02-25DOI: 10.1101/2021.02.24.432346
Muwei Li, Yurui Gao, Z. Ding, J. Gore
Significance This work reports our discoveries on the power spectra of functional MRI signals in white matter under resting state. Interestingly, the unique and repeatable features in the power spectra we observed are consistently found to coincide with locations of particular structural organizations in deep white matter. Close scrutiny into the functional signal profiles reveals distinct hemodynamic responses in these locations, which reflects unique neurovascular and anatomical configurations therein. Findings from this work add to the existing understanding of blood-oxygen-level–dependent changes during resting state and reveal a strong structural-vascular-functional association in white matter. Accurate characterization of the time courses of blood-oxygen-level–dependent (BOLD) signal changes is crucial for the analysis and interpretation of functional MRI data. While several studies have shown that white matter (WM) exhibits distinct BOLD responses evoked by tasks, there have been no comprehensive investigations into the time courses of spontaneous signal fluctuations in WM. We measured the power spectra of the resting-state time courses in a set of regions within WM identified as showing synchronous signals using independent components analysis. In each component, a clear separation between voxels into two categories was evident, based on their power spectra: one group exhibited a single peak, and the other had an additional peak at a higher frequency. Their groupings are location specific, and their distributions reflect unique neurovascular and anatomical configurations. Importantly, the two categories of voxels differed in their engagement in functional integration, revealed by differences in the number of interregional connections based on the two categories separately. Taken together, these findings suggest WM signals are heterogeneous in nature and depend on local structural-vascular-functional associations.
{"title":"Power spectra reveal distinct BOLD resting-state time courses in white matter","authors":"Muwei Li, Yurui Gao, Z. Ding, J. Gore","doi":"10.1101/2021.02.24.432346","DOIUrl":"https://doi.org/10.1101/2021.02.24.432346","url":null,"abstract":"Significance This work reports our discoveries on the power spectra of functional MRI signals in white matter under resting state. Interestingly, the unique and repeatable features in the power spectra we observed are consistently found to coincide with locations of particular structural organizations in deep white matter. Close scrutiny into the functional signal profiles reveals distinct hemodynamic responses in these locations, which reflects unique neurovascular and anatomical configurations therein. Findings from this work add to the existing understanding of blood-oxygen-level–dependent changes during resting state and reveal a strong structural-vascular-functional association in white matter. Accurate characterization of the time courses of blood-oxygen-level–dependent (BOLD) signal changes is crucial for the analysis and interpretation of functional MRI data. While several studies have shown that white matter (WM) exhibits distinct BOLD responses evoked by tasks, there have been no comprehensive investigations into the time courses of spontaneous signal fluctuations in WM. We measured the power spectra of the resting-state time courses in a set of regions within WM identified as showing synchronous signals using independent components analysis. In each component, a clear separation between voxels into two categories was evident, based on their power spectra: one group exhibited a single peak, and the other had an additional peak at a higher frequency. Their groupings are location specific, and their distributions reflect unique neurovascular and anatomical configurations. Importantly, the two categories of voxels differed in their engagement in functional integration, revealed by differences in the number of interregional connections based on the two categories separately. Taken together, these findings suggest WM signals are heterogeneous in nature and depend on local structural-vascular-functional associations.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83447220","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 : 2021-02-25DOI: 10.1101/2021.02.25.432939
Yangyang Lin, S. Grinter, Zhongju Lu, Xianjin Xu, H. Z. Wang, Hongwu Liang, Panpan Hou, Junyuan Gao, C. Clausen, Jingyi Shi, Wenshan Zhao, Zhiwei Ma, Yongfeng Liu, K. M. White, Lu Zhao, P. Kang, Guohui Zhang, I. Cohen, X. Zou, J. Cui
Significance C28, a chemical compound identified by computational screening, selectively facilitates voltage-dependent activation of a cardiac potassium ion channel, IKs. This compound reverses drug-induced prolongation of the electric signals across the cardiac cell membrane known as action potentials (APs) but minimally affects the normal AP at the same dosage. This outcome supports a computational prediction that enhancing voltage-dependent activation of IKs could be a potential therapy for AP prolongation. This therapy would increase the safety and expand the therapeutic efficacy of many currently approved drugs that induce AP prolongation, which can trigger life-threatening cardiac arrhythmias. Cardiac arrhythmias are the most common cause of sudden cardiac death worldwide. Lengthening the ventricular action potential duration (APD), either congenitally or via pathologic or pharmacologic means, predisposes to a life-threatening ventricular arrhythmia, Torsade de Pointes. IKs (KCNQ1+KCNE1), a slowly activating K+ current, plays a role in action potential repolarization. In this study, we screened a chemical library in silico by docking compounds to the voltage-sensing domain (VSD) of the IKs channel. Here, we show that C28 specifically shifted IKs VSD activation in ventricle to more negative voltages and reversed the drug-induced lengthening of APD. At the same dosage, C28 did not cause significant changes of the normal APD in either ventricle or atrium. This study provides evidence in support of a computational prediction of IKs VSD activation as a potential therapeutic approach for all forms of APD prolongation. This outcome could expand the therapeutic efficacy of a myriad of currently approved drugs that may trigger arrhythmias.
{"title":"Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects","authors":"Yangyang Lin, S. Grinter, Zhongju Lu, Xianjin Xu, H. Z. Wang, Hongwu Liang, Panpan Hou, Junyuan Gao, C. Clausen, Jingyi Shi, Wenshan Zhao, Zhiwei Ma, Yongfeng Liu, K. M. White, Lu Zhao, P. Kang, Guohui Zhang, I. Cohen, X. Zou, J. Cui","doi":"10.1101/2021.02.25.432939","DOIUrl":"https://doi.org/10.1101/2021.02.25.432939","url":null,"abstract":"Significance C28, a chemical compound identified by computational screening, selectively facilitates voltage-dependent activation of a cardiac potassium ion channel, IKs. This compound reverses drug-induced prolongation of the electric signals across the cardiac cell membrane known as action potentials (APs) but minimally affects the normal AP at the same dosage. This outcome supports a computational prediction that enhancing voltage-dependent activation of IKs could be a potential therapy for AP prolongation. This therapy would increase the safety and expand the therapeutic efficacy of many currently approved drugs that induce AP prolongation, which can trigger life-threatening cardiac arrhythmias. Cardiac arrhythmias are the most common cause of sudden cardiac death worldwide. Lengthening the ventricular action potential duration (APD), either congenitally or via pathologic or pharmacologic means, predisposes to a life-threatening ventricular arrhythmia, Torsade de Pointes. IKs (KCNQ1+KCNE1), a slowly activating K+ current, plays a role in action potential repolarization. In this study, we screened a chemical library in silico by docking compounds to the voltage-sensing domain (VSD) of the IKs channel. Here, we show that C28 specifically shifted IKs VSD activation in ventricle to more negative voltages and reversed the drug-induced lengthening of APD. At the same dosage, C28 did not cause significant changes of the normal APD in either ventricle or atrium. This study provides evidence in support of a computational prediction of IKs VSD activation as a potential therapeutic approach for all forms of APD prolongation. This outcome could expand the therapeutic efficacy of a myriad of currently approved drugs that may trigger arrhythmias.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91259347","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 : 2021-02-24DOI: 10.1101/2021.02.24.432718
Tianyou Yao, Seth T. Coleman, Thu Vu Phuc Nguyen, I. Golding, O. Igoshin
Significance Viral dormancy, in which the infected cell is not killed but rather becomes the long-term residence of the parasite, is a hallmark of viruses across kingdoms from bacteriophages to HIV. When and how viruses decide to opt for this lifestyle remains mysterious. Phage lambda, which serves as a paradigm for viral dormancy, is reported to count the number of coinfecting viruses and then uses this value to assess the abundance of potential hosts and decide whether to become dormant. Here, we use a single-cell measurement of viruses and messenger RNA together with mathematical modeling to illuminate how lambda performs this task. When host cells are in low abundance, temperate bacteriophages opt for dormant (lysogenic) infection. Phage lambda implements this strategy by increasing the frequency of lysogeny at higher multiplicity of infection (MOI). However, it remains unclear how the phage reliably counts infecting viral genomes even as their intracellular number increases because of replication. By combining theoretical modeling with single-cell measurements of viral copy number and gene expression, we find that instead of hindering lambda’s decision, replication facilitates it. In a nonreplicating mutant, viral gene expression simply scales with MOI rather than diverging into lytic (virulent) and lysogenic trajectories. A similar pattern is followed during early infection by wild-type phage. However, later in the infection, the modulation of viral replication by the decision genes amplifies the initially modest gene expression differences into divergent trajectories. Replication thus ensures the optimal decision—lysis upon single-phage infection and lysogeny at higher MOI.
{"title":"Bacteriophage self-counting in the presence of viral replication","authors":"Tianyou Yao, Seth T. Coleman, Thu Vu Phuc Nguyen, I. Golding, O. Igoshin","doi":"10.1101/2021.02.24.432718","DOIUrl":"https://doi.org/10.1101/2021.02.24.432718","url":null,"abstract":"Significance Viral dormancy, in which the infected cell is not killed but rather becomes the long-term residence of the parasite, is a hallmark of viruses across kingdoms from bacteriophages to HIV. When and how viruses decide to opt for this lifestyle remains mysterious. Phage lambda, which serves as a paradigm for viral dormancy, is reported to count the number of coinfecting viruses and then uses this value to assess the abundance of potential hosts and decide whether to become dormant. Here, we use a single-cell measurement of viruses and messenger RNA together with mathematical modeling to illuminate how lambda performs this task. When host cells are in low abundance, temperate bacteriophages opt for dormant (lysogenic) infection. Phage lambda implements this strategy by increasing the frequency of lysogeny at higher multiplicity of infection (MOI). However, it remains unclear how the phage reliably counts infecting viral genomes even as their intracellular number increases because of replication. By combining theoretical modeling with single-cell measurements of viral copy number and gene expression, we find that instead of hindering lambda’s decision, replication facilitates it. In a nonreplicating mutant, viral gene expression simply scales with MOI rather than diverging into lytic (virulent) and lysogenic trajectories. A similar pattern is followed during early infection by wild-type phage. However, later in the infection, the modulation of viral replication by the decision genes amplifies the initially modest gene expression differences into divergent trajectories. Replication thus ensures the optimal decision—lysis upon single-phage infection and lysogeny at higher MOI.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"118 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90606513","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 : 2021-02-22DOI: 10.1101/2021.02.22.432296
Florent Figon, I. Hurbain, Xavier Heiligenstein, S. Trépout, K. Medjoubi, A. Somogyi, C. Delevoye, G. Raposo, Jérôme Casas
Significance Pigment–light interactions have shaped animal evolution, from vision to camouflage. How organisms cope with harmful photodegradative products while maintaining pigment-bearing cell integrity, from skin to light screening in eyes, remains mysterious. We studied color-changing crab spiders to unravel the intracellular mechanisms leading to within-cell formation and degradation of pigment organelles. We found that they belong to the widespread lysosome-related organelle family, like vertebrate melanosomes. The endolysosomal system allows reversible coloration in spiders by sustaining pigment turnover thanks to its fundamental anabolic and catabolic functions, a hypothesis first laid out for human eyes. Our findings imply that the ubiquitous endolysosomal system had been repurposed early in animal evolution to handle pigment–light interactions, providing phenotypic plasticity and cell function maintenance. Pigment organelles of vertebrates belong to the lysosome-related organelle (LRO) family, of which melanin-producing melanosomes are the prototypes. While their anabolism has been extensively unraveled through the study of melanosomes in skin melanocytes, their catabolism remains poorly known. Here, we tap into the unique ability of crab spiders to reversibly change body coloration to examine the catabolism of their pigment organelles. By combining ultrastructural and metal analyses on high-pressure frozen integuments, we first assess whether pigment organelles of crab spiders belong to the LRO family and second, how their catabolism is intracellularly processed. Using scanning transmission electron microscopy, electron tomography, and nanoscale Synchrotron-based scanning X-ray fluorescence, we show that pigment organelles possess ultrastructural and chemical hallmarks of LROs, including intraluminal vesicles and metal deposits, similar to melanosomes. Monitoring ultrastructural changes during bleaching suggests that the catabolism of pigment organelles involves the degradation and removal of their intraluminal content, possibly through lysosomal mechanisms. In contrast to skin melanosomes, anabolism and catabolism of pigments proceed within the same cell without requiring either cell death or secretion/phagocytosis. Our work hence provides support for the hypothesis that the endolysosomal system is fully functionalized for within-cell turnover of pigments, leading to functional maintenance under adverse conditions and phenotypic plasticity. First formulated for eye melanosomes in the context of human vision, the hypothesis of intracellular turnover of pigments gets unprecedented strong support from pigment organelles of spiders.
{"title":"Catabolism of lysosome-related organelles in color-changing spiders supports intracellular turnover of pigments","authors":"Florent Figon, I. Hurbain, Xavier Heiligenstein, S. Trépout, K. Medjoubi, A. Somogyi, C. Delevoye, G. Raposo, Jérôme Casas","doi":"10.1101/2021.02.22.432296","DOIUrl":"https://doi.org/10.1101/2021.02.22.432296","url":null,"abstract":"Significance Pigment–light interactions have shaped animal evolution, from vision to camouflage. How organisms cope with harmful photodegradative products while maintaining pigment-bearing cell integrity, from skin to light screening in eyes, remains mysterious. We studied color-changing crab spiders to unravel the intracellular mechanisms leading to within-cell formation and degradation of pigment organelles. We found that they belong to the widespread lysosome-related organelle family, like vertebrate melanosomes. The endolysosomal system allows reversible coloration in spiders by sustaining pigment turnover thanks to its fundamental anabolic and catabolic functions, a hypothesis first laid out for human eyes. Our findings imply that the ubiquitous endolysosomal system had been repurposed early in animal evolution to handle pigment–light interactions, providing phenotypic plasticity and cell function maintenance. Pigment organelles of vertebrates belong to the lysosome-related organelle (LRO) family, of which melanin-producing melanosomes are the prototypes. While their anabolism has been extensively unraveled through the study of melanosomes in skin melanocytes, their catabolism remains poorly known. Here, we tap into the unique ability of crab spiders to reversibly change body coloration to examine the catabolism of their pigment organelles. By combining ultrastructural and metal analyses on high-pressure frozen integuments, we first assess whether pigment organelles of crab spiders belong to the LRO family and second, how their catabolism is intracellularly processed. Using scanning transmission electron microscopy, electron tomography, and nanoscale Synchrotron-based scanning X-ray fluorescence, we show that pigment organelles possess ultrastructural and chemical hallmarks of LROs, including intraluminal vesicles and metal deposits, similar to melanosomes. Monitoring ultrastructural changes during bleaching suggests that the catabolism of pigment organelles involves the degradation and removal of their intraluminal content, possibly through lysosomal mechanisms. In contrast to skin melanosomes, anabolism and catabolism of pigments proceed within the same cell without requiring either cell death or secretion/phagocytosis. Our work hence provides support for the hypothesis that the endolysosomal system is fully functionalized for within-cell turnover of pigments, leading to functional maintenance under adverse conditions and phenotypic plasticity. First formulated for eye melanosomes in the context of human vision, the hypothesis of intracellular turnover of pigments gets unprecedented strong support from pigment organelles of spiders.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"76 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83871918","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 : 2021-02-21DOI: 10.1101/2021.02.20.432121
Zhuoyi Liang, Vipul Kumar, M. Le Bouteiller, Jeffrey Zurita, Josefin Kenrick, Sherry G. Lin, Jiangman Lou, Jianqiao Hu, A. Y. Ye, C. Boboila, F. Alt, Richard L. Frock
Significance Alternative end joining (A-EJ) is implicated in oncogenic translocations and mediating DNA double-strand-break (DSB) repair in cycling cells when classical nonhomologous end-joining (C-NHEJ) factors of the C-NHEJ ligase complex are absent. However, V(D)J recombination-associated DSBs that occur in G1 cell cycle-phase progenitor lymphocytes are joined exclusively by the C-NHEJ pathway. Until now, however, the overall mechanisms that join general DSBs in G1-phase progenitor B cells had not been fully elucidated. Here, we report that Ku, a core C-NHEJ DSB recognition complex, directs repair of a variety of different targeted DSBs toward C-NHEJ and suppresses A-EJ in G1-phase cells. We suggest this Ku activity explains how Ku deficiency can rescue the neuronal development and embryonic lethality phenotype of ligase 4-deficient mice. Classical nonhomologous end joining (C-NHEJ) repairs DNA double-strand breaks (DSBs) throughout interphase but predominates in G1 phase when homologous recombination is unavailable. Complexes containing the Ku70/80 (“Ku”) and XRCC4/ligase IV (Lig4) core C-NHEJ factors are required, respectively, for sensing and joining DSBs. While XRCC4/Lig4 are absolutely required for joining RAG1/2 endonuclease (“RAG”)-initiated DSBs during V(D)J recombination in G1-phase progenitor lymphocytes, cycling cells deficient for XRCC4/Lig4 also can join chromosomal DSBs by alternative end-joining (A-EJ) pathways. Restriction of V(D)J recombination by XRCC4/Lig4-mediated joining has been attributed to RAG shepherding V(D)J DSBs exclusively into the C-NHEJ pathway. Here, we report that A-EJ of DSB ends generated by RAG1/2, Cas9:gRNA, and Zinc finger endonucleases in Lig4-deficient G1-arrested progenitor B cell lines is suppressed by Ku. Thus, while diverse DSBs remain largely as free broken ends in Lig4-deficient G1-arrested progenitor B cells, deletion of Ku70 increases DSB rejoining and translocation levels to those observed in Ku70-deficient counterparts. Correspondingly, while RAG-initiated V(D)J DSB joining is abrogated in Lig4-deficient G1-arrested progenitor B cell lines, joining of RAG-generated DSBs in Ku70-deficient and Ku70/Lig4 double-deficient lines occurs through a translocation-like A-EJ mechanism. Thus, in G1-arrested, Lig4-deficient progenitor B cells are functionally end-joining suppressed due to Ku-dependent blockage of A-EJ, potentially in association with G1-phase down-regulation of Lig1. Finally, we suggest that differential impacts of Ku deficiency versus Lig4 deficiency on V(D)J recombination, neuronal apoptosis, and embryonic development results from Ku-mediated inhibition of A-EJ in the G1 cell cycle phase in Lig4-deficient developing lymphocyte and neuronal cells.
{"title":"Ku70 suppresses alternative end joining in G1-arrested progenitor B cells","authors":"Zhuoyi Liang, Vipul Kumar, M. Le Bouteiller, Jeffrey Zurita, Josefin Kenrick, Sherry G. Lin, Jiangman Lou, Jianqiao Hu, A. Y. Ye, C. Boboila, F. Alt, Richard L. Frock","doi":"10.1101/2021.02.20.432121","DOIUrl":"https://doi.org/10.1101/2021.02.20.432121","url":null,"abstract":"Significance Alternative end joining (A-EJ) is implicated in oncogenic translocations and mediating DNA double-strand-break (DSB) repair in cycling cells when classical nonhomologous end-joining (C-NHEJ) factors of the C-NHEJ ligase complex are absent. However, V(D)J recombination-associated DSBs that occur in G1 cell cycle-phase progenitor lymphocytes are joined exclusively by the C-NHEJ pathway. Until now, however, the overall mechanisms that join general DSBs in G1-phase progenitor B cells had not been fully elucidated. Here, we report that Ku, a core C-NHEJ DSB recognition complex, directs repair of a variety of different targeted DSBs toward C-NHEJ and suppresses A-EJ in G1-phase cells. We suggest this Ku activity explains how Ku deficiency can rescue the neuronal development and embryonic lethality phenotype of ligase 4-deficient mice. Classical nonhomologous end joining (C-NHEJ) repairs DNA double-strand breaks (DSBs) throughout interphase but predominates in G1 phase when homologous recombination is unavailable. Complexes containing the Ku70/80 (“Ku”) and XRCC4/ligase IV (Lig4) core C-NHEJ factors are required, respectively, for sensing and joining DSBs. While XRCC4/Lig4 are absolutely required for joining RAG1/2 endonuclease (“RAG”)-initiated DSBs during V(D)J recombination in G1-phase progenitor lymphocytes, cycling cells deficient for XRCC4/Lig4 also can join chromosomal DSBs by alternative end-joining (A-EJ) pathways. Restriction of V(D)J recombination by XRCC4/Lig4-mediated joining has been attributed to RAG shepherding V(D)J DSBs exclusively into the C-NHEJ pathway. Here, we report that A-EJ of DSB ends generated by RAG1/2, Cas9:gRNA, and Zinc finger endonucleases in Lig4-deficient G1-arrested progenitor B cell lines is suppressed by Ku. Thus, while diverse DSBs remain largely as free broken ends in Lig4-deficient G1-arrested progenitor B cells, deletion of Ku70 increases DSB rejoining and translocation levels to those observed in Ku70-deficient counterparts. Correspondingly, while RAG-initiated V(D)J DSB joining is abrogated in Lig4-deficient G1-arrested progenitor B cell lines, joining of RAG-generated DSBs in Ku70-deficient and Ku70/Lig4 double-deficient lines occurs through a translocation-like A-EJ mechanism. Thus, in G1-arrested, Lig4-deficient progenitor B cells are functionally end-joining suppressed due to Ku-dependent blockage of A-EJ, potentially in association with G1-phase down-regulation of Lig1. Finally, we suggest that differential impacts of Ku deficiency versus Lig4 deficiency on V(D)J recombination, neuronal apoptosis, and embryonic development results from Ku-mediated inhibition of A-EJ in the G1 cell cycle phase in Lig4-deficient developing lymphocyte and neuronal cells.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75648444","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 : 2021-02-19DOI: 10.1101/2021.02.19.432005
M. R. Zeronian, O. Klykov, Júlia Portell i de Montserrat, Maria J. Konijnenberg, Anamika Gaur, R. Scheltema, B. Janssen
Significance Communication between cells is essential for the development and homeostasis of tissues and prevents diseases, including cancers. The Notch and Jagged transmembrane proteins interact to regulate cell–cell communication in all multicellular animals. Defining their interactions is critical to understand Notch-associated disorders. While structural studies have focused on short regions of both proteins, it is unclear how their entire extracellular domains collectively engage to activate signaling. Here, we identify several unreported, interacting regions in the Notch1–Jagged1 full extracellular complex. We show that Notch1 and Jagged1 ectodomains are not fully extended and reveal that activation-determining regions, previously thought to be distal, engage directly. This interaction network redefines our knowledge on Notch activation and provides avenues for therapeutic advances. The Notch signaling system links cellular fate to that of its neighbors, driving proliferation, apoptosis, and cell differentiation in metazoans, whereas dysfunction leads to debilitating developmental disorders and cancers. Other than a five-by-five domain complex, it is unclear how the 40 extracellular domains of the Notch1 receptor collectively engage the 19 domains of its canonical ligand, Jagged1, to activate Notch1 signaling. Here, using cross-linking mass spectrometry (XL-MS), biophysical, and structural techniques on the full extracellular complex and targeted sites, we identify five distinct regions, two on Notch1 and three on Jagged1, that form an interaction network. The Notch1 membrane–proximal regulatory region individually binds to the established Notch1 epidermal growth factor (EGF) 8–EGF13 and Jagged1 C2–EGF3 activation sites as well as to two additional Jagged1 regions, EGF8–EGF11 and cysteine-rich domain. XL-MS and quantitative interaction experiments show that the three Notch1-binding sites on Jagged1 also engage intramolecularly. These interactions, together with Notch1 and Jagged1 ectodomain dimensions and flexibility, determined by small-angle X-ray scattering, support the formation of nonlinear architectures. Combined, the data suggest that critical Notch1 and Jagged1 regions are not distal but engage directly to control Notch1 signaling, thereby redefining the Notch1–Jagged1 activation mechanism and indicating routes for therapeutic applications.
{"title":"Notch–Jagged signaling complex defined by an interaction mosaic","authors":"M. R. Zeronian, O. Klykov, Júlia Portell i de Montserrat, Maria J. Konijnenberg, Anamika Gaur, R. Scheltema, B. Janssen","doi":"10.1101/2021.02.19.432005","DOIUrl":"https://doi.org/10.1101/2021.02.19.432005","url":null,"abstract":"Significance Communication between cells is essential for the development and homeostasis of tissues and prevents diseases, including cancers. The Notch and Jagged transmembrane proteins interact to regulate cell–cell communication in all multicellular animals. Defining their interactions is critical to understand Notch-associated disorders. While structural studies have focused on short regions of both proteins, it is unclear how their entire extracellular domains collectively engage to activate signaling. Here, we identify several unreported, interacting regions in the Notch1–Jagged1 full extracellular complex. We show that Notch1 and Jagged1 ectodomains are not fully extended and reveal that activation-determining regions, previously thought to be distal, engage directly. This interaction network redefines our knowledge on Notch activation and provides avenues for therapeutic advances. The Notch signaling system links cellular fate to that of its neighbors, driving proliferation, apoptosis, and cell differentiation in metazoans, whereas dysfunction leads to debilitating developmental disorders and cancers. Other than a five-by-five domain complex, it is unclear how the 40 extracellular domains of the Notch1 receptor collectively engage the 19 domains of its canonical ligand, Jagged1, to activate Notch1 signaling. Here, using cross-linking mass spectrometry (XL-MS), biophysical, and structural techniques on the full extracellular complex and targeted sites, we identify five distinct regions, two on Notch1 and three on Jagged1, that form an interaction network. The Notch1 membrane–proximal regulatory region individually binds to the established Notch1 epidermal growth factor (EGF) 8–EGF13 and Jagged1 C2–EGF3 activation sites as well as to two additional Jagged1 regions, EGF8–EGF11 and cysteine-rich domain. XL-MS and quantitative interaction experiments show that the three Notch1-binding sites on Jagged1 also engage intramolecularly. These interactions, together with Notch1 and Jagged1 ectodomain dimensions and flexibility, determined by small-angle X-ray scattering, support the formation of nonlinear architectures. Combined, the data suggest that critical Notch1 and Jagged1 regions are not distal but engage directly to control Notch1 signaling, thereby redefining the Notch1–Jagged1 activation mechanism and indicating routes for therapeutic applications.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"62 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89486320","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 : 2021-02-17DOI: 10.1101/2021.02.17.431682
Qiuting Zhang, Jian Li, Japinder S. Nijjer, Haoran Lu, Mrityunjay Kothari, Ricard Alert, T. Cohen, Jing Yan
Significance Biofilms are microbial cities in which bacterial cells reside in a polymeric matrix. They are commonly found inside soft confining environments such as food matrices and host tissues, against which bacteria must push to proliferate. Here, by combining single-cell live imaging and mechanical characterization, we show that the confining environment determines the dynamics of biofilm shape and internal structure. The self-organization of biofilm architecture is caused by force transmission between the environment and the biofilm, mediated by the extracellular matrix secreted by the cells. Our findings lead to a better understanding of how bacterial communities develop under mechanical constraints, and potentially to strategies for preventing and controlling biofilm growth in three-dimensional environments. Biofilms are aggregates of bacterial cells surrounded by an extracellular matrix. Much progress has been made in studying biofilm growth on solid substrates; however, little is known about the biophysical mechanisms underlying biofilm development in three-dimensional confined environments in which the biofilm-dwelling cells must push against and even damage the surrounding environment to proliferate. Here, combining single-cell imaging, mutagenesis, and rheological measurement, we reveal the key morphogenesis steps of Vibrio cholerae biofilms embedded in hydrogels as they grow by four orders of magnitude from their initial size. We show that the morphodynamics and cell ordering in embedded biofilms are fundamentally different from those of biofilms on flat surfaces. Treating embedded biofilms as inclusions growing in an elastic medium, we quantitatively show that the stiffness contrast between the biofilm and its environment determines biofilm morphology and internal architecture, selecting between spherical biofilms with no cell ordering and oblate ellipsoidal biofilms with high cell ordering. When embedded in stiff gels, cells self-organize into a bipolar structure that resembles the molecular ordering in nematic liquid crystal droplets. In vitro biomechanical analysis shows that cell ordering arises from stress transmission across the biofilm–environment interface, mediated by specific matrix components. Our imaging technique and theoretical approach are generalizable to other biofilm-forming species and potentially to biofilms embedded in mucus or host tissues as during infection. Our results open an avenue to understand how confined cell communities grow by means of a compromise between their inherent developmental program and the mechanical constraints imposed by the environment.
{"title":"Morphogenesis and cell ordering in confined bacterial biofilms","authors":"Qiuting Zhang, Jian Li, Japinder S. Nijjer, Haoran Lu, Mrityunjay Kothari, Ricard Alert, T. Cohen, Jing Yan","doi":"10.1101/2021.02.17.431682","DOIUrl":"https://doi.org/10.1101/2021.02.17.431682","url":null,"abstract":"Significance Biofilms are microbial cities in which bacterial cells reside in a polymeric matrix. They are commonly found inside soft confining environments such as food matrices and host tissues, against which bacteria must push to proliferate. Here, by combining single-cell live imaging and mechanical characterization, we show that the confining environment determines the dynamics of biofilm shape and internal structure. The self-organization of biofilm architecture is caused by force transmission between the environment and the biofilm, mediated by the extracellular matrix secreted by the cells. Our findings lead to a better understanding of how bacterial communities develop under mechanical constraints, and potentially to strategies for preventing and controlling biofilm growth in three-dimensional environments. Biofilms are aggregates of bacterial cells surrounded by an extracellular matrix. Much progress has been made in studying biofilm growth on solid substrates; however, little is known about the biophysical mechanisms underlying biofilm development in three-dimensional confined environments in which the biofilm-dwelling cells must push against and even damage the surrounding environment to proliferate. Here, combining single-cell imaging, mutagenesis, and rheological measurement, we reveal the key morphogenesis steps of Vibrio cholerae biofilms embedded in hydrogels as they grow by four orders of magnitude from their initial size. We show that the morphodynamics and cell ordering in embedded biofilms are fundamentally different from those of biofilms on flat surfaces. Treating embedded biofilms as inclusions growing in an elastic medium, we quantitatively show that the stiffness contrast between the biofilm and its environment determines biofilm morphology and internal architecture, selecting between spherical biofilms with no cell ordering and oblate ellipsoidal biofilms with high cell ordering. When embedded in stiff gels, cells self-organize into a bipolar structure that resembles the molecular ordering in nematic liquid crystal droplets. In vitro biomechanical analysis shows that cell ordering arises from stress transmission across the biofilm–environment interface, mediated by specific matrix components. Our imaging technique and theoretical approach are generalizable to other biofilm-forming species and potentially to biofilms embedded in mucus or host tissues as during infection. Our results open an avenue to understand how confined cell communities grow by means of a compromise between their inherent developmental program and the mechanical constraints imposed by the environment.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74540868","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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