Pub Date : 2024-09-06DOI: 10.1093/pnasnexus/pgae387
David M Markowitz
This paper evaluated the effectiveness of using generative AI to simplify science communication and enhance the public’s understanding of science. By comparing lay summaries of journal articles from PNAS, yoked to those generated by AI, this work first assessed linguistic simplicity differences across such summaries and public perceptions in follow-up experiments. Specifically, Study 1a analyzed simplicity features of PNAS abstracts (scientific summaries) and significance statements (lay summaries), observing that lay summaries were indeed linguistically simpler, but effect size differences were small. Study 1b used a large language model, GPT-4, to create significance statements based on paper abstracts and this more than doubled the average effect size without fine-tuning. Study 2 experimentally demonstrated that simply-written GPT summaries facilitated more favorable perceptions of scientists (they were perceived as more credible and trustworthy, but less intelligent) than more complexly-written human PNAS summaries. Crucially, Study 3 experimentally demonstrated that participants comprehended scientific writing better after reading simple GPT summaries compared to complex PNAS summaries. In their own words, participants also summarized scientific papers in a more detailed and concrete manner after reading GPT summaries compared to PNAS summaries of the same article. AI has the potential to engage scientific communities and the public via a simple language heuristic, advocating for its integration into scientific dissemination for a more informed society.
{"title":"From complexity to clarity: How AI enhances perceptions of scientists and the public’s understanding of science","authors":"David M Markowitz","doi":"10.1093/pnasnexus/pgae387","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae387","url":null,"abstract":"This paper evaluated the effectiveness of using generative AI to simplify science communication and enhance the public’s understanding of science. By comparing lay summaries of journal articles from PNAS, yoked to those generated by AI, this work first assessed linguistic simplicity differences across such summaries and public perceptions in follow-up experiments. Specifically, Study 1a analyzed simplicity features of PNAS abstracts (scientific summaries) and significance statements (lay summaries), observing that lay summaries were indeed linguistically simpler, but effect size differences were small. Study 1b used a large language model, GPT-4, to create significance statements based on paper abstracts and this more than doubled the average effect size without fine-tuning. Study 2 experimentally demonstrated that simply-written GPT summaries facilitated more favorable perceptions of scientists (they were perceived as more credible and trustworthy, but less intelligent) than more complexly-written human PNAS summaries. Crucially, Study 3 experimentally demonstrated that participants comprehended scientific writing better after reading simple GPT summaries compared to complex PNAS summaries. In their own words, participants also summarized scientific papers in a more detailed and concrete manner after reading GPT summaries compared to PNAS summaries of the same article. AI has the potential to engage scientific communities and the public via a simple language heuristic, advocating for its integration into scientific dissemination for a more informed society.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1093/pnasnexus/pgae389
Mingxi Yang, David Moffat, Yuanxu Dong, Jean-Raymond Bidlot
Understanding processes driving air-sea gas transfer and being able to model both its mean and variability are critical for studies of climate and carbon cycle. The air-sea gas transfer velocity (K660) is almost universally parameterized as a function of wind speed in large scale models – an oversimplification that buries the mechanisms controlling K660 and neglects much natural variability. Sea state has long been speculated to affect gas transfer, but consistent relationships from in situ observations have been elusive. Here, applying a Machine Learning technique to an updated compilation of shipboard direct observations of the CO2 transfer velocity (KCO2,660), we show that the inclusion of significant wave height improves the model simulation of KCO2,660, while parameters such as wave age, wave steepness, and swell-wind directional difference have little influence on KCO2,660. Wind history is found to be important, as in high seas KCO2,660 during periods of falling winds exceed periods of rising winds by ∼20% in the mean. This hysteresis in KCO2,660 is consistent with the development of waves and increase in whitecap coverage as the seas mature. A similar hysteresis is absent from the transfer of a more soluble gas, confirming that the sea state dependence in KCO2,660 is primarily due to bubble-mediated gas transfer upon wave breaking. We propose a new parameterization of KCO2,660 as a function of wind stress and significant wave height, which resemble observed KCO2,660 both in the mean and on short timescales.
{"title":"Deciphering the variability in air-sea gas transfer due to sea state and wind history","authors":"Mingxi Yang, David Moffat, Yuanxu Dong, Jean-Raymond Bidlot","doi":"10.1093/pnasnexus/pgae389","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae389","url":null,"abstract":"Understanding processes driving air-sea gas transfer and being able to model both its mean and variability are critical for studies of climate and carbon cycle. The air-sea gas transfer velocity (K660) is almost universally parameterized as a function of wind speed in large scale models – an oversimplification that buries the mechanisms controlling K660 and neglects much natural variability. Sea state has long been speculated to affect gas transfer, but consistent relationships from in situ observations have been elusive. Here, applying a Machine Learning technique to an updated compilation of shipboard direct observations of the CO2 transfer velocity (KCO2,660), we show that the inclusion of significant wave height improves the model simulation of KCO2,660, while parameters such as wave age, wave steepness, and swell-wind directional difference have little influence on KCO2,660. Wind history is found to be important, as in high seas KCO2,660 during periods of falling winds exceed periods of rising winds by ∼20% in the mean. This hysteresis in KCO2,660 is consistent with the development of waves and increase in whitecap coverage as the seas mature. A similar hysteresis is absent from the transfer of a more soluble gas, confirming that the sea state dependence in KCO2,660 is primarily due to bubble-mediated gas transfer upon wave breaking. We propose a new parameterization of KCO2,660 as a function of wind stress and significant wave height, which resemble observed KCO2,660 both in the mean and on short timescales.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04DOI: 10.1093/pnasnexus/pgae377
Anna Paola Muntoni, Fabio Mazza, Alfredo Braunstein, Giovanni Catania, Luca Dall'Asta
The recent COVID-19 pandemic underscores the significance of early-stage non-pharmacological intervention strategies. The widespread use of masks and the systematic implementation of contact tracing strategies provide a potentially equally effective and socially less impactful alternative to more conventional approaches, such as large-scale mobility restrictions. However, manual contact tracing faces strong limitations in accessing the network of contacts, and the scalability of currently implemented protocols for smartphone-based digital contact tracing becomes impractical during the rapid expansion phases of the outbreaks, due to the surge in exposure notifications and associated tests. A substantial improvement in digital contact tracing can be obtained through the integration of probabilistic techniques for risk assessment that can more effectively guide the allocation of new diagnostic tests. In this study, we first quantitatively analyze the diagnostic and social costs associated with these containment measures based on contact tracing, employing three state-of-the-art models of SARS-CoV-2 spreading. Our results suggest that probabilistic techniques allow for more effective mitigation at a lower cost. Secondly, our findings reveal a remarkable efficacy of probabilistic contact-tracing techniques in performing backward and multi-step tracing and capturing super-spreading events.
{"title":"Effectiveness of probabilistic contact tracing in epidemic containment: The role of super-spreaders and transmission path reconstruction","authors":"Anna Paola Muntoni, Fabio Mazza, Alfredo Braunstein, Giovanni Catania, Luca Dall'Asta","doi":"10.1093/pnasnexus/pgae377","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae377","url":null,"abstract":"The recent COVID-19 pandemic underscores the significance of early-stage non-pharmacological intervention strategies. The widespread use of masks and the systematic implementation of contact tracing strategies provide a potentially equally effective and socially less impactful alternative to more conventional approaches, such as large-scale mobility restrictions. However, manual contact tracing faces strong limitations in accessing the network of contacts, and the scalability of currently implemented protocols for smartphone-based digital contact tracing becomes impractical during the rapid expansion phases of the outbreaks, due to the surge in exposure notifications and associated tests. A substantial improvement in digital contact tracing can be obtained through the integration of probabilistic techniques for risk assessment that can more effectively guide the allocation of new diagnostic tests. In this study, we first quantitatively analyze the diagnostic and social costs associated with these containment measures based on contact tracing, employing three state-of-the-art models of SARS-CoV-2 spreading. Our results suggest that probabilistic techniques allow for more effective mitigation at a lower cost. Secondly, our findings reveal a remarkable efficacy of probabilistic contact-tracing techniques in performing backward and multi-step tracing and capturing super-spreading events.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1093/pnasnexus/pgae382
Sandy A Slovikosky, Robert A Montgomery
Large mammals respond to human hunting via proactive and reactive responses, which can induce subsequent non-consumptive effects (NCEs). Thus, there is evidence that large mammals exhibit considerable behavioral plasticity in response to human hunting risk. Currently, however, it is unclear which cues of human hunting large mammals may be responding to. We conducted a literature review to quantify the large mammal behavioral responses induced by the cues of human hunting. We detected 106 studies published between 1978 and 2022 of which 34 (32%) included at least one measure of cue, typically visual (n = 26 of 106, 25%) or auditory (n = 11 of 106, 10%). Space use (n = 37 of 106, 35%) and flight (n = 31 of 106, 29%) were the most common behavioral responses studied. Among the 34 studies that assessed at least one cue, six (18%) measured large mammal behavioral responses in relation to proxies of human hunting (e.g., hunting site or season). Only 14% (n = 15 of 106) of the studies quantified an NCE associated with an animal’s response to human hunting. Moreover, the association between cues measured and antipredator behaviors is unclear due to a consistent lack of controls. Thus, while human hunting can shape animal populations via consumptive effects, the cues triggering these responses are poorly understood. There hence remains a need to link cues, responses, NCEs, and the dynamics of large mammal populations. Human activities can then be adjusted accordingly to prevent both overexploitation and unintended NCEs in animal populations.
{"title":"Large mammal behavioral defenses induced by the cues of human predation","authors":"Sandy A Slovikosky, Robert A Montgomery","doi":"10.1093/pnasnexus/pgae382","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae382","url":null,"abstract":"Large mammals respond to human hunting via proactive and reactive responses, which can induce subsequent non-consumptive effects (NCEs). Thus, there is evidence that large mammals exhibit considerable behavioral plasticity in response to human hunting risk. Currently, however, it is unclear which cues of human hunting large mammals may be responding to. We conducted a literature review to quantify the large mammal behavioral responses induced by the cues of human hunting. We detected 106 studies published between 1978 and 2022 of which 34 (32%) included at least one measure of cue, typically visual (n = 26 of 106, 25%) or auditory (n = 11 of 106, 10%). Space use (n = 37 of 106, 35%) and flight (n = 31 of 106, 29%) were the most common behavioral responses studied. Among the 34 studies that assessed at least one cue, six (18%) measured large mammal behavioral responses in relation to proxies of human hunting (e.g., hunting site or season). Only 14% (n = 15 of 106) of the studies quantified an NCE associated with an animal’s response to human hunting. Moreover, the association between cues measured and antipredator behaviors is unclear due to a consistent lack of controls. Thus, while human hunting can shape animal populations via consumptive effects, the cues triggering these responses are poorly understood. There hence remains a need to link cues, responses, NCEs, and the dynamics of large mammal populations. Human activities can then be adjusted accordingly to prevent both overexploitation and unintended NCEs in animal populations.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1093/pnasnexus/pgae381
Aleksandra Tymoszewska, Tamara Aleksandrzak-Piekarczyk
The bacterial mannose phosphotransferase system (Man-PTS) mediates uptake of selected monosaccharides. Simultaneously, it is a receptor for diverse bacteriocins such as subclass IIa pediocin-like bacteriocins and some subclass IId ones (garvicins ABCQ, lactococcins ABZ, BacSJ, ubericin K, and angicin). So far, no attempt has been made to categorize this ever-expanding group of bacteriocins. Here, we identified Man-PTS as a receptor for a number of novel bacteriocins and demonstrated that they all belong to a large family of Man-PTS-binding non-pediocin-like peptides. Based on amino acid sequence similarities between members of this family, we propose their classification into five groups. This classification conveniently distinguishes bacteriocins with specific structures and properties regarding their spectrum of antimicrobial activity and pattern of interaction with Man-PTS. With respect to the latter, we indicate individual amino acid residues or regions of Man-PTS and the bacteriocin responsible for their interaction. In Man-PTS these residues localize to the exterior of the transport complex, specifically the extracellular loop of the so-called Vmotif domain containing regions γ and/or γ+, and to the interior of the transport complex, specifically the interface between the Core and Vmotif domains. Finally, we propose that while the bacteriocins from separate groups display specific binding patterns to Man-PTS, the general mechanism of their interaction with the receptor is universal despite significant differences in their predicted structures, i.e., after initial docking on the bacterial cell through an interaction with the Man-PTS regions γ and/or γ+, they pull away its Core and Vmotif from one another to form a pore across the membrane.
{"title":"Subclass IId bacteriocins targeting Man-PTS—structural diversity and implications for receptor interaction and antimicrobial activity","authors":"Aleksandra Tymoszewska, Tamara Aleksandrzak-Piekarczyk","doi":"10.1093/pnasnexus/pgae381","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae381","url":null,"abstract":"The bacterial mannose phosphotransferase system (Man-PTS) mediates uptake of selected monosaccharides. Simultaneously, it is a receptor for diverse bacteriocins such as subclass IIa pediocin-like bacteriocins and some subclass IId ones (garvicins ABCQ, lactococcins ABZ, BacSJ, ubericin K, and angicin). So far, no attempt has been made to categorize this ever-expanding group of bacteriocins. Here, we identified Man-PTS as a receptor for a number of novel bacteriocins and demonstrated that they all belong to a large family of Man-PTS-binding non-pediocin-like peptides. Based on amino acid sequence similarities between members of this family, we propose their classification into five groups. This classification conveniently distinguishes bacteriocins with specific structures and properties regarding their spectrum of antimicrobial activity and pattern of interaction with Man-PTS. With respect to the latter, we indicate individual amino acid residues or regions of Man-PTS and the bacteriocin responsible for their interaction. In Man-PTS these residues localize to the exterior of the transport complex, specifically the extracellular loop of the so-called Vmotif domain containing regions γ and/or γ+, and to the interior of the transport complex, specifically the interface between the Core and Vmotif domains. Finally, we propose that while the bacteriocins from separate groups display specific binding patterns to Man-PTS, the general mechanism of their interaction with the receptor is universal despite significant differences in their predicted structures, i.e., after initial docking on the bacterial cell through an interaction with the Man-PTS regions γ and/or γ+, they pull away its Core and Vmotif from one another to form a pore across the membrane.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196251","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}
Current infertility treatment strategies focus on mature gametes, leaving a significant proportion of cases with gamete progenitors that stopped complete differentiation. On the other hand, recent advancements in next generation sequencing have identified many candidate genes that may promote maturation of germ cells. Although gene therapy has shown success in mice, concerns about the integration of DNA vectors into oocytes hinder clinical applications. Here, we present the restoration of fertility in female mice through Sendai virus (SeV)-mediated RNA delivery. Ovaries lacking Kitl expression exhibit only primordial follicles due to impaired signaling to oocytes expressing the KIT tyrosine kinase. Despite SeVs being immunogenic and larger than the blood-follicle barrier, the administration of Kitl-expressing SeVs reinitiated oogenesis in genetically infertile mice that have only primordial follicles, resulting in the birth of normal offspring through natural mating. This virus also effectively addressed iatrogenic infertility induced by busulfan, a widely used cancer chemotherapy agent. Offspring born through SeV administration and natural mating displayed normal genomic imprinting patterns and fertility. Since SeVs pose no genotoxicity risk, the successful restoration of fertility by SeVs represents a promising approach for treating congenital infertility with somatic cell defects and protecting fertility of cancer patients who may become infertile due to loss of oocytes during cancer therapy.
目前的不孕症治疗策略主要针对成熟的配子，因此有相当一部分病例的配子祖细胞停止了完全分化。另一方面，下一代测序技术的最新进展发现了许多可能促进生殖细胞成熟的候选基因。虽然基因治疗在小鼠身上取得了成功，但 DNA 载体整合到卵母细胞中的问题阻碍了临床应用。在这里，我们介绍了通过仙台病毒（SeV）介导的 RNA 递送恢复雌性小鼠生育能力的方法。由于向表达 KIT 酪氨酸激酶的卵母细胞发出的信号受损，缺乏 Kitl 表达的卵巢只表现出原始卵泡。尽管 SeVs 具有免疫原性，且体积大于血-卵泡屏障，但给只有原始卵泡的遗传性不育小鼠注射表达 Kitl 的 SeVs 后，小鼠的卵子生成得以恢复，并通过自然交配产下了正常的后代。这种病毒还有效地解决了广泛使用的癌症化疗药物--丁硫克百威（busulfan）诱发的先天性不孕症。通过 SeV 给药和自然交配出生的后代显示出正常的基因组印记模式和生育能力。由于 SeV 没有遗传毒性风险，因此 SeV 成功恢复生育能力是治疗体细胞缺陷先天性不孕症和保护癌症患者生育能力的一种有前途的方法。
{"title":"Sendai virus-mediated RNA delivery restores fertility to congenital and chemotherapy-induced infertile female mice","authors":"Mito Kanatsu-Shinohara, Hiroko Morimoto, Tianjiao Liu, Masaru Tamura, Takashi Shinohara","doi":"10.1093/pnasnexus/pgae375","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae375","url":null,"abstract":"Current infertility treatment strategies focus on mature gametes, leaving a significant proportion of cases with gamete progenitors that stopped complete differentiation. On the other hand, recent advancements in next generation sequencing have identified many candidate genes that may promote maturation of germ cells. Although gene therapy has shown success in mice, concerns about the integration of DNA vectors into oocytes hinder clinical applications. Here, we present the restoration of fertility in female mice through Sendai virus (SeV)-mediated RNA delivery. Ovaries lacking Kitl expression exhibit only primordial follicles due to impaired signaling to oocytes expressing the KIT tyrosine kinase. Despite SeVs being immunogenic and larger than the blood-follicle barrier, the administration of Kitl-expressing SeVs reinitiated oogenesis in genetically infertile mice that have only primordial follicles, resulting in the birth of normal offspring through natural mating. This virus also effectively addressed iatrogenic infertility induced by busulfan, a widely used cancer chemotherapy agent. Offspring born through SeV administration and natural mating displayed normal genomic imprinting patterns and fertility. Since SeVs pose no genotoxicity risk, the successful restoration of fertility by SeVs represents a promising approach for treating congenital infertility with somatic cell defects and protecting fertility of cancer patients who may become infertile due to loss of oocytes during cancer therapy.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1093/pnasnexus/pgae376
Jonas Bafna-Rührer, Yashomangalam D Bhutada, Jean V Orth, Süleyman Øzmerih, Lei Yang, Daniel Zielinski, Suresh Sudarsan
Engineering microbial cells for the commercial production of biomolecules and biochemicals requires understanding how cells respond to dynamically changing substrate (feast-famine) conditions in industrial-scale bioreactors. Scale-down methods that oscillate substrate are commonly applied to predict the industrial-scale behavior of microbes. We followed a compartment-modeling approach to design a scale-down method based on the simulation of an industrial-scale bioreactor. This study uses high-cell-density scale-down experiments to investigate E. coli knockout strains of five major glucose-sensitive transcription factors (Cra, Crp, FliA, PrpR, RpoS) to study their regulatory role during glucose oscillations. RNA-sequencing analysis revealed that the glucose oscillations caused the downregulation of several stress-related functions in E. coli. An in-depth analysis of strain physiology and transcriptome revealed a distinct phenotype of the strains tested under glucose oscillations. Specifically, the knockout strains of Cra, Crp, and RpoS resulted in a more sensitive transcriptional response than the control strain, while the knockouts of FliA and PrpR responded less severely. These findings imply that the regulation orchestrated by Cra, Crp, and RpoS may be essential for robust E. coli production strains. In contrast, the regulation by FliA and PrpR may be undesirable for temporal oscillations in glucose availability.
{"title":"Repeated glucose oscillations in high-cell-density cultures influence stress-related functions of Escherichia coli","authors":"Jonas Bafna-Rührer, Yashomangalam D Bhutada, Jean V Orth, Süleyman Øzmerih, Lei Yang, Daniel Zielinski, Suresh Sudarsan","doi":"10.1093/pnasnexus/pgae376","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae376","url":null,"abstract":"Engineering microbial cells for the commercial production of biomolecules and biochemicals requires understanding how cells respond to dynamically changing substrate (feast-famine) conditions in industrial-scale bioreactors. Scale-down methods that oscillate substrate are commonly applied to predict the industrial-scale behavior of microbes. We followed a compartment-modeling approach to design a scale-down method based on the simulation of an industrial-scale bioreactor. This study uses high-cell-density scale-down experiments to investigate E. coli knockout strains of five major glucose-sensitive transcription factors (Cra, Crp, FliA, PrpR, RpoS) to study their regulatory role during glucose oscillations. RNA-sequencing analysis revealed that the glucose oscillations caused the downregulation of several stress-related functions in E. coli. An in-depth analysis of strain physiology and transcriptome revealed a distinct phenotype of the strains tested under glucose oscillations. Specifically, the knockout strains of Cra, Crp, and RpoS resulted in a more sensitive transcriptional response than the control strain, while the knockouts of FliA and PrpR responded less severely. These findings imply that the regulation orchestrated by Cra, Crp, and RpoS may be essential for robust E. coli production strains. In contrast, the regulation by FliA and PrpR may be undesirable for temporal oscillations in glucose availability.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1093/pnasnexus/pgae374
Rajkamal Srivastava, Coral González-Prieto, Jason P Lynch, Michele Muscolo, Catherine Y Lin, Markus A Brown, Luisa Lemos, Anishma Shrestha, Marcia S Osburne, John M Leong, Cammie F Lesser
Engineered smart microbes that deliver therapeutic payloads are emerging as treatment modalities, particularly for diseases with links to the gastrointestinal tract. Enterohemorrhagic E coli (EHEC) is a causative agent of potentially lethal hemolytic uremic syndrome. Given concerns that antibiotic treatment increases EHEC production of Shiga toxin (Stx), which is responsible for systemic disease, novel remedies are needed. EHEC encodes a type III secretion system (T3SS) that injects Tir into enterocytes. Tir inserts into the host cell membrane, exposing an extracellular domain that subsequently binds intimin, one of its outer membrane proteins, triggering the formation of attaching and effacing (A/E) lesions that promote EHEC mucosal colonization. Citrobacter rodentium (Cr), a natural A/E mouse pathogen, similarly requires Tir and intimin for its pathogenesis. Mice infected with Cr(ΦStx2dact), a variant lysogenized with an EHEC-derived phage that produces Stx2dact, develop intestinal A/E lesions and toxin-dependent disease. Stx2a is more closely associated with human disease. By developing an efficient approach to seamlessly modify the C. rodentium genome, we generated Cr_Tir-MEHEC(ΦStx2a), a variant that expresses Stx2a and the EHEC extracellular Tir domain. We found that mouse pre-colonization with HS-PROT3EcT-TD4, a human commensal E. coli strain (E. coli HS) engineered to efficiently secrete- an anti-EHEC Tir nanobody, delayed bacterial colonization and improved survival after challenge with Cr_Tir-MEHEC(ΦStx2a). This study provides the first evidence to support the efficacy of engineered commensal E. coli to intestinally deliver therapeutic payloads that block essential enteric pathogen virulence determinants, a strategy that may serve as an antibiotic-independent antibacterial therapeutic modality.
可投放治疗载荷的工程智能微生物正成为一种新兴的治疗方式，尤其是针对与胃肠道有关的疾病。肠出血性大肠杆菌（EHEC）是潜在致命性溶血性尿毒症的致病菌。鉴于抗生素治疗会增加 EHEC 产生志贺毒素（Stx），而志贺毒素会导致全身性疾病，因此需要新的治疗方法。EHEC 编码一种 III 型分泌系统（T3SS），可将 Tir 注入肠细胞。Tir 插入宿主细胞膜，暴露出一个细胞外结构域，该结构域随后会与其外膜蛋白之一 intimin 结合，引发附着和脱落（A/E）病变的形成，从而促进 EHEC 黏膜定植。鼠柠檬杆菌（Citrobacter rodentium，Cr）是一种天然的 A/E小鼠病原体，它的致病过程同样需要 Tir 和 intimin。小鼠感染 Cr(ΦStx2dact)后，会出现肠道 A/E 病变和毒素依赖性疾病。Stx2a 与人类疾病的关系更为密切。通过开发无缝修改 C. rodentium 基因组的有效方法，我们产生了 Cr_Tir-MEHEC(ΦStx2a)，一种表达 Stx2a 和 EHEC 细胞外 Tir 结构域的变体。我们发现，小鼠在接受 Cr_Tir-MEHEC(ΦStx2a)挑战后，用 HS-PROT3EcT-TD4（一种经改造能有效分泌抗 EHEC Tir 纳米抗体的人类共生大肠杆菌菌株（大肠杆菌 HS））进行预定植能延缓细菌定植并提高存活率。这项研究首次证明了工程共生大肠杆菌在肠道内输送阻断肠道病原体毒力决定因子的治疗载荷的有效性，这种策略可作为一种抗生素无关的抗菌治疗模式。
{"title":"In situ deposition of nanobodies by an engineered commensal microbe promotes survival in a mouse model of enterohemorrhagic E. coli","authors":"Rajkamal Srivastava, Coral González-Prieto, Jason P Lynch, Michele Muscolo, Catherine Y Lin, Markus A Brown, Luisa Lemos, Anishma Shrestha, Marcia S Osburne, John M Leong, Cammie F Lesser","doi":"10.1093/pnasnexus/pgae374","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae374","url":null,"abstract":"Engineered smart microbes that deliver therapeutic payloads are emerging as treatment modalities, particularly for diseases with links to the gastrointestinal tract. Enterohemorrhagic E coli (EHEC) is a causative agent of potentially lethal hemolytic uremic syndrome. Given concerns that antibiotic treatment increases EHEC production of Shiga toxin (Stx), which is responsible for systemic disease, novel remedies are needed. EHEC encodes a type III secretion system (T3SS) that injects Tir into enterocytes. Tir inserts into the host cell membrane, exposing an extracellular domain that subsequently binds intimin, one of its outer membrane proteins, triggering the formation of attaching and effacing (A/E) lesions that promote EHEC mucosal colonization. Citrobacter rodentium (Cr), a natural A/E mouse pathogen, similarly requires Tir and intimin for its pathogenesis. Mice infected with Cr(ΦStx2dact), a variant lysogenized with an EHEC-derived phage that produces Stx2dact, develop intestinal A/E lesions and toxin-dependent disease. Stx2a is more closely associated with human disease. By developing an efficient approach to seamlessly modify the C. rodentium genome, we generated Cr_Tir-MEHEC(ΦStx2a), a variant that expresses Stx2a and the EHEC extracellular Tir domain. We found that mouse pre-colonization with HS-PROT3EcT-TD4, a human commensal E. coli strain (E. coli HS) engineered to efficiently secrete- an anti-EHEC Tir nanobody, delayed bacterial colonization and improved survival after challenge with Cr_Tir-MEHEC(ΦStx2a). This study provides the first evidence to support the efficacy of engineered commensal E. coli to intestinally deliver therapeutic payloads that block essential enteric pathogen virulence determinants, a strategy that may serve as an antibiotic-independent antibacterial therapeutic modality.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196253","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 : 2024-08-30DOI: 10.1093/pnasnexus/pgae357
Shannon C Kelly, Cassandra B Higgins, Jiameng Sun, Joshua A Adams, Yiming Zhang, Samuel Ballentine, Yong Miao, XiaoXia Cui, Małgorzata Milewska, Ilona Wandzik, Jun Yoshino, Benjamin M Swarts, Shun-ichi Wada, Brian J DeBosch
The matrix metalloproteinase MMP14 is a ubiquitously expressed, membrane-bound, secreted endopeptidase that proteolyzes substrates to regulate development, signaling, and metabolism. However, the spatial and contextual events inciting MMP14 activation, and its metabolic sequelae are not fully understood. Here, we introduce an inducible, hepatocyte-specific MMP14-deficient model (MMP14LKO mice) to elucidate cell-intrinsic and systemic MMP14 function. We show that hepatocyte MMP14 mediates diet-induced body-weight gain, peripheral adiposity, and impaired glucose homeostasis, and drives diet-induced liver TG accumulation, and induction of hepatic inflammatory and fibrotic gene expression. Single-nucleus RNA sequencing revealed that hepatocyte MMP14 mediates Kupffer and T cell accumulation and promotes diet-induced hepatocellular sub-population shifts toward protection against lipid absorption. MMP14 co-immunoprecipitation and proteomic analyses revealed MMP14 substrate binding across both inflammatory and cytokine signaling, as well as metabolic pathways. Strikingly, hepatocyte MMP14 loss-of-function suppressed skeletal muscle and adipose inflammation in vivo, and in a reductionist adipose-hepatocyte co-culture model. Finally, we reveal that trehalose-type glucose transporter inhibitors decrease hepatocyte MMP14 gene expression and nominate these inhibitors as translatable therapeutic metabolic agents. We conclude that hepatocyte MMP14 drives liver and inter-organ inflammatory and metabolic sequelae of obesigenic dietary insult. Modulating MMP14 activation and blockade thus represents a targetable node in the pathogenesis of hepatic inflammation.
{"title":"Hepatocyte MMP14 mediates liver and inter-organ inflammatory responses to diet-induced liver injury","authors":"Shannon C Kelly, Cassandra B Higgins, Jiameng Sun, Joshua A Adams, Yiming Zhang, Samuel Ballentine, Yong Miao, XiaoXia Cui, Małgorzata Milewska, Ilona Wandzik, Jun Yoshino, Benjamin M Swarts, Shun-ichi Wada, Brian J DeBosch","doi":"10.1093/pnasnexus/pgae357","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae357","url":null,"abstract":"The matrix metalloproteinase MMP14 is a ubiquitously expressed, membrane-bound, secreted endopeptidase that proteolyzes substrates to regulate development, signaling, and metabolism. However, the spatial and contextual events inciting MMP14 activation, and its metabolic sequelae are not fully understood. Here, we introduce an inducible, hepatocyte-specific MMP14-deficient model (MMP14LKO mice) to elucidate cell-intrinsic and systemic MMP14 function. We show that hepatocyte MMP14 mediates diet-induced body-weight gain, peripheral adiposity, and impaired glucose homeostasis, and drives diet-induced liver TG accumulation, and induction of hepatic inflammatory and fibrotic gene expression. Single-nucleus RNA sequencing revealed that hepatocyte MMP14 mediates Kupffer and T cell accumulation and promotes diet-induced hepatocellular sub-population shifts toward protection against lipid absorption. MMP14 co-immunoprecipitation and proteomic analyses revealed MMP14 substrate binding across both inflammatory and cytokine signaling, as well as metabolic pathways. Strikingly, hepatocyte MMP14 loss-of-function suppressed skeletal muscle and adipose inflammation in vivo, and in a reductionist adipose-hepatocyte co-culture model. Finally, we reveal that trehalose-type glucose transporter inhibitors decrease hepatocyte MMP14 gene expression and nominate these inhibitors as translatable therapeutic metabolic agents. We conclude that hepatocyte MMP14 drives liver and inter-organ inflammatory and metabolic sequelae of obesigenic dietary insult. Modulating MMP14 activation and blockade thus represents a targetable node in the pathogenesis of hepatic inflammation.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196254","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 : 2024-08-30DOI: 10.1093/pnasnexus/pgae360
Kwun Yip Fung, Zong-Liang Yang, Alberto Martilli, E Scott Krayenhoff, Dev Niyogi
We utilized city-scale simulations to quantitatively compare the diverse urban overheating mitigation strategies, specifically tied to social vulnerability and their cooling efficacies during heatwaves. We enhanced the Weather Research and Forecasting model to encompass the urban tree effect and calculate Universal Thermal Climate Index for assessing thermal comfort. Taking Houston, Texas, U.S. as an example, the study reveals that equitably mitigating urban overheat is achievable by considering the city’s demographic composition and physical structure. Study results show that while urban trees may yield less cooling impact (0.27 K of Universal Thermal Climate Index in daytime) relative to cool roofs (0.30 K), the urban trees strategy can emerge as an effective approach for enhancing community resilience in heat stress-related outcomes. Social vulnerability-based heat mitigation was reviewed as Vulnerability-Weighted Daily Cumulative Heat Stress Change. Results underscore: (i) importance of considering the community resilience when evaluating heat mitigation impact, and (ii) the need to assess planting spaces for urban trees, rooftop areas, and neighborhood vulnerability when designing community-oriented urban overheating mitigation strategies.
{"title":"Prioritizing social vulnerability in urban heat mitigation","authors":"Kwun Yip Fung, Zong-Liang Yang, Alberto Martilli, E Scott Krayenhoff, Dev Niyogi","doi":"10.1093/pnasnexus/pgae360","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae360","url":null,"abstract":"We utilized city-scale simulations to quantitatively compare the diverse urban overheating mitigation strategies, specifically tied to social vulnerability and their cooling efficacies during heatwaves. We enhanced the Weather Research and Forecasting model to encompass the urban tree effect and calculate Universal Thermal Climate Index for assessing thermal comfort. Taking Houston, Texas, U.S. as an example, the study reveals that equitably mitigating urban overheat is achievable by considering the city’s demographic composition and physical structure. Study results show that while urban trees may yield less cooling impact (0.27 K of Universal Thermal Climate Index in daytime) relative to cool roofs (0.30 K), the urban trees strategy can emerge as an effective approach for enhancing community resilience in heat stress-related outcomes. Social vulnerability-based heat mitigation was reviewed as Vulnerability-Weighted Daily Cumulative Heat Stress Change. Results underscore: (i) importance of considering the community resilience when evaluating heat mitigation impact, and (ii) the need to assess planting spaces for urban trees, rooftop areas, and neighborhood vulnerability when designing community-oriented urban overheating mitigation strategies.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196273","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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