Pub Date : 2023-11-14DOI: 10.1101/2023.11.14.566891
Daniel M Williams, Andrew A Peden
NLRP3 is an inflammasome seeding pattern recognition receptor activated in response to multiple danger signals which perturb intracellular homeostasis. Electrostatic interactions between the NLRP3 polybasic (PB) region and negatively charged lipids on the trans-Golgi network (TGN) have been proposed to recruit NLRP3 to the TGN. In this study, we demonstrate that membrane association of NLRP3 is critically dependant on S-acylation of a highly conserved cysteine residue (Cys-130), which traps NLRP3 in a dynamic S-acylation cycle at the Golgi, and a series of hydrophobic residues preceding Cys-130 which act in conjunction with the PB region to facilitate Cys-130 dependent Golgi enrichment. Due to segregation from Golgi localised thioesterase enzymes caused by a nigericin induced breakdown in Golgi trafficking, NLRP3 becomes immobilised on the Golgi through reduced de-acylation of its Cys-130 lipid anchor, suggesting that disruptions in Golgi homeostasis are conveyed to NLRP3 through its acylation state. Thus, our work defines a nigericin sensitive S-acylation cycle that gates access of NLRP3 to the Golgi.
{"title":"S-acylation of NLRP3 provides a nigericin sensitive gating mechanism that controls access to the Golgi","authors":"Daniel M Williams, Andrew A Peden","doi":"10.1101/2023.11.14.566891","DOIUrl":"https://doi.org/10.1101/2023.11.14.566891","url":null,"abstract":"NLRP3 is an inflammasome seeding pattern recognition receptor activated in response to multiple danger signals which perturb intracellular homeostasis. Electrostatic interactions between the NLRP3 polybasic (PB) region and negatively charged lipids on the trans-Golgi network (TGN) have been proposed to recruit NLRP3 to the TGN. In this study, we demonstrate that membrane association of NLRP3 is critically dependant on S-acylation of a highly conserved cysteine residue (Cys-130), which traps NLRP3 in a dynamic S-acylation cycle at the Golgi, and a series of hydrophobic residues preceding Cys-130 which act in conjunction with the PB region to facilitate Cys-130 dependent Golgi enrichment. Due to segregation from Golgi localised thioesterase enzymes caused by a nigericin induced breakdown in Golgi trafficking, NLRP3 becomes immobilised on the Golgi through reduced de-acylation of its Cys-130 lipid anchor, suggesting that disruptions in Golgi homeostasis are conveyed to NLRP3 through its acylation state. Thus, our work defines a nigericin sensitive S-acylation cycle that gates access of NLRP3 to the Golgi.","PeriodicalId":486943,"journal":{"name":"bioRxiv (Cold Spring Harbor Laboratory)","volume":"23 8","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134954046","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 : 2023-11-14DOI: 10.1101/2023.11.10.566585
Yufan Zhou, Tian Li, Zhijing He, Lavanya Choppavarapu, Xiaohui Hu, Gustavo Leone, Michael Kahn, Victor X. Jin
The therapeutic potential of targeting the β-catenin/CBP interaction has been demonstrated in a variety of preclinical tumor models with a small molecule inhibitor, ICG-001, characterized as a β-catenin/CBP antagonist. Despite the high binding specificity of ICG- 001 for the N-terminus of CBP, this β-catenin/CBP antagonist exhibits pleiotropic effects. Our recent studies found global changes in three-dimensional (3D) chromatin architecture in response to disruption of the β-catenin/CBP interaction in pancreatic cancer cells. However, an understanding of the functional crosstalk between antagonizing the β-catenin/CBP interaction effect changes in 3D chromatin architecture and thereby gene expression and downstream effects remains to be elucidated. Here we perform Hi-C analyses on canonical and patient-derived pancreatic cancer cells before and after the treatment with ICG-001. In addition to global alteration of 3D chromatin domains, we unexpectedly identify insulin signaling genes enriched in the altered chromatin domains. We further demonstrate the chromatin loops associated with insulin signaling genes are significantly weakened after ICG-001 treatment. We finally elicit the deletion of a looping of IRS1, a key insulin signaling gene, significantly impede pancreatic cancer cell growth, indicating that looping-mediated insulin signaling might act as an oncogenic pathway to promote pancreatic cancer progression. Our work shows that targeting aberrant insulin chromatin looping in pancreatic cancer might provide a therapeutic benefit.
{"title":"Reprogramming of 3D chromatin domains by antagonizing the β-catenin/CBP interaction attenuates insulin signaling in pancreatic cancer","authors":"Yufan Zhou, Tian Li, Zhijing He, Lavanya Choppavarapu, Xiaohui Hu, Gustavo Leone, Michael Kahn, Victor X. Jin","doi":"10.1101/2023.11.10.566585","DOIUrl":"https://doi.org/10.1101/2023.11.10.566585","url":null,"abstract":"The therapeutic potential of targeting the β-catenin/CBP interaction has been demonstrated in a variety of preclinical tumor models with a small molecule inhibitor, ICG-001, characterized as a β-catenin/CBP antagonist. Despite the high binding specificity of ICG- 001 for the N-terminus of CBP, this β-catenin/CBP antagonist exhibits pleiotropic effects. Our recent studies found global changes in three-dimensional (3D) chromatin architecture in response to disruption of the β-catenin/CBP interaction in pancreatic cancer cells. However, an understanding of the functional crosstalk between antagonizing the β-catenin/CBP interaction effect changes in 3D chromatin architecture and thereby gene expression and downstream effects remains to be elucidated. Here we perform Hi-C analyses on canonical and patient-derived pancreatic cancer cells before and after the treatment with ICG-001. In addition to global alteration of 3D chromatin domains, we unexpectedly identify insulin signaling genes enriched in the altered chromatin domains. We further demonstrate the chromatin loops associated with insulin signaling genes are significantly weakened after ICG-001 treatment. We finally elicit the deletion of a looping of IRS1, a key insulin signaling gene, significantly impede pancreatic cancer cell growth, indicating that looping-mediated insulin signaling might act as an oncogenic pathway to promote pancreatic cancer progression. Our work shows that targeting aberrant insulin chromatin looping in pancreatic cancer might provide a therapeutic benefit.","PeriodicalId":486943,"journal":{"name":"bioRxiv (Cold Spring Harbor Laboratory)","volume":"29 11","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134954550","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 : 2023-11-14DOI: 10.1101/2023.11.14.567044
Nour El Husseini, Solomon A. Mekonnen, Cherisse L Hall, Stephanie J Cole, Jared A Carter, Ashton T. Belew, Najib M. El-Sayed, Vincent T Lee
Pseudomonas aeruginosa is an opportunistic nosocomial pathogen responsible for catheter-associated urinary tract infections (CAUTI). In a murine model of P. aeruginosa CAUTI, we previously demonstrated that urea within urine suppresses quorum sensing and induces the Entner-Douderoff (E-D) pathway. The E-D pathway consists of the genes zwf , pgl , edd , and eda . Zwf and Pgl convert glucose-6-phosphate into 6-phosphogluconate. Edd hydrolyzes 6-phosphogluconate to 2-keto-3-deoxy-6-phosphogluconate (KDPG). Finally, Eda cleaves KDPG to glyceraldehyde-3-phosphate and pyruvate, which enters the citric acid cycle. Here, we generated in-frame E-D mutants in strain PA14 and assessed their growth phenotypes on chemically defined media. These E-D mutants have a growth defect when grown on glucose or gluconate as sole carbon source which are similar to results previously reported for PAO1 mutants lacking E-D genes. RNA-sequencing following short exposure to urine revealed minimal gene regulation differences compared to the wild type. In a murine CAUTI model, virulence testing of E-D mutants revealed that two mutants lacking zwf and pgl showed minor fitness defects. Infection with the pgl strain exhibited a 20% increase in host survival, and the zwf strain displayed decreased colonization of the catheter and kidneys. Consequently, our findings suggest that the E-D pathway in P. aeruginosa is dispensable in this model of CAUTI.
{"title":"Characterization of the Entner-Douderoff Pathway in<i>Pseudomonas aeruginosa</i>Catheter-associated Urinary Tract Infections","authors":"Nour El Husseini, Solomon A. Mekonnen, Cherisse L Hall, Stephanie J Cole, Jared A Carter, Ashton T. Belew, Najib M. El-Sayed, Vincent T Lee","doi":"10.1101/2023.11.14.567044","DOIUrl":"https://doi.org/10.1101/2023.11.14.567044","url":null,"abstract":"Pseudomonas aeruginosa is an opportunistic nosocomial pathogen responsible for catheter-associated urinary tract infections (CAUTI). In a murine model of P. aeruginosa CAUTI, we previously demonstrated that urea within urine suppresses quorum sensing and induces the Entner-Douderoff (E-D) pathway. The E-D pathway consists of the genes zwf , pgl , edd , and eda . Zwf and Pgl convert glucose-6-phosphate into 6-phosphogluconate. Edd hydrolyzes 6-phosphogluconate to 2-keto-3-deoxy-6-phosphogluconate (KDPG). Finally, Eda cleaves KDPG to glyceraldehyde-3-phosphate and pyruvate, which enters the citric acid cycle. Here, we generated in-frame E-D mutants in strain PA14 and assessed their growth phenotypes on chemically defined media. These E-D mutants have a growth defect when grown on glucose or gluconate as sole carbon source which are similar to results previously reported for PAO1 mutants lacking E-D genes. RNA-sequencing following short exposure to urine revealed minimal gene regulation differences compared to the wild type. In a murine CAUTI model, virulence testing of E-D mutants revealed that two mutants lacking zwf and pgl showed minor fitness defects. Infection with the pgl strain exhibited a 20% increase in host survival, and the zwf strain displayed decreased colonization of the catheter and kidneys. Consequently, our findings suggest that the E-D pathway in P. aeruginosa is dispensable in this model of CAUTI.","PeriodicalId":486943,"journal":{"name":"bioRxiv (Cold Spring Harbor Laboratory)","volume":"48 24","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991314","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 : 2023-11-14DOI: 10.1101/2023.11.12.566771
Corbett Bennett, Ben Ouellette, Tamina K Ramirez, Alex Cahoon, Hannah Cabasco, Hannah Belski, Ryan Gillis, Conor Grasso, Robert Howard, Tye Johnson, Henry Loeffler, Heston Smith, David Sullivan, Allison Williford, Shiella Caldejon, Severine Durand, Samuel D Gale, Alan Guthrie, Vivian Ha, Warren Han, Ben Hardcastle, Ethan McBride, Chris Mochizuki, Arjun Sridhar, Lucas Suarez, Jackie Swapp, Josh Wilkes, Colin Farrell, Peter Groblewski, Shawn Olsen
To understand the neural basis of behavior, it is essential to measure spiking dynamics across many interacting brain regions. While new technology, such as Neuropixels probes, facilitates multi-regional recordings, significant surgical and procedural hurdles remain for these experiments to achieve their full potential. Here, we describe a novel 3D-printed cranial implant for electrophysiological recordings from distributed areas of the mouse brain. The skull-shaped implant is designed with customizable insertion holes, allowing targeting of dozens of cortical and subcortical structures in single mice. We demonstrate the procedure's high success rate, implant biocompatibility, lack of adverse effects on behavior training, compatibility with optical imaging and optogenetics, and repeated high-quality Neuropixels recordings over multiple days. To showcase the scientific utility of this new methodology, we use multi-probe recordings to reveal how alpha rhythms organize spiking activity across visual and sensorimotor networks. Overall, this methodology enables powerful large-scale electrophysiological measurements for the study of distributed computation in the mouse brain.
{"title":"SHIELD: Skull-shaped hemispheric implants enabling large-scale-electrophysiology datasets in the mouse brain","authors":"Corbett Bennett, Ben Ouellette, Tamina K Ramirez, Alex Cahoon, Hannah Cabasco, Hannah Belski, Ryan Gillis, Conor Grasso, Robert Howard, Tye Johnson, Henry Loeffler, Heston Smith, David Sullivan, Allison Williford, Shiella Caldejon, Severine Durand, Samuel D Gale, Alan Guthrie, Vivian Ha, Warren Han, Ben Hardcastle, Ethan McBride, Chris Mochizuki, Arjun Sridhar, Lucas Suarez, Jackie Swapp, Josh Wilkes, Colin Farrell, Peter Groblewski, Shawn Olsen","doi":"10.1101/2023.11.12.566771","DOIUrl":"https://doi.org/10.1101/2023.11.12.566771","url":null,"abstract":"To understand the neural basis of behavior, it is essential to measure spiking dynamics across many interacting brain regions. While new technology, such as Neuropixels probes, facilitates multi-regional recordings, significant surgical and procedural hurdles remain for these experiments to achieve their full potential. Here, we describe a novel 3D-printed cranial implant for electrophysiological recordings from distributed areas of the mouse brain. The skull-shaped implant is designed with customizable insertion holes, allowing targeting of dozens of cortical and subcortical structures in single mice. We demonstrate the procedure's high success rate, implant biocompatibility, lack of adverse effects on behavior training, compatibility with optical imaging and optogenetics, and repeated high-quality Neuropixels recordings over multiple days. To showcase the scientific utility of this new methodology, we use multi-probe recordings to reveal how alpha rhythms organize spiking activity across visual and sensorimotor networks. Overall, this methodology enables powerful large-scale electrophysiological measurements for the study of distributed computation in the mouse brain.","PeriodicalId":486943,"journal":{"name":"bioRxiv (Cold Spring Harbor Laboratory)","volume":"44 23","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991611","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 : 2023-11-14DOI: 10.1101/2023.11.14.566986
Saurabh S. Dhakar, Albert Galera-Prat, Lari Lehtiö
ADP-ribosyltransferases PARP1 and PARP2 play a major role in DNA repair mechanism by detecting the DNA damage and inducing poly-ADP-ribosylation dependent chromatin relaxation and recruitment of repair proteins. Catalytic PARP inhibitors are used as anticancer drugs especially in the case of tumors arising from sensitizing mutations. Recently, a study showed that Histone PARylation Factor (HPF1) forms a joint active site with PARP1/2. The interaction of HPF1 with PARP1/2 alters the automodification site from Aspartate, Glutamate to Serine, which has been shown to be a key ADP-ribosylation event in the context of DNA damage. Therefore disruption of PARP1/2-HPF1 interaction could be an alternative strategy for drug development to block the PARP1/2 activity. In this study, we describe a FRET based high-throughput screening assay to screen inhibitor libraries against PARP-HPF1 interaction. We optimized the conditions for FRET signal and verified the interaction by competing the FRET pair in multiple ways. The assay is robust and easy to automate. Validatory screening showed the robust performance of the assay, and we discovered two compounds, Dimethylacrylshikonin and Alkannin, with μM inhibition potency against PARP1/2-HPF1 interaction. The assay will facilitate the discovery of inhibitors against HPF1-PARP1/2 complex and to develop potentially new effective anticancer agents.
{"title":"High-throughput screening assay for PARP-HPF1 interaction inhibitors to affect DNA damage repair","authors":"Saurabh S. Dhakar, Albert Galera-Prat, Lari Lehtiö","doi":"10.1101/2023.11.14.566986","DOIUrl":"https://doi.org/10.1101/2023.11.14.566986","url":null,"abstract":"ADP-ribosyltransferases PARP1 and PARP2 play a major role in DNA repair mechanism by detecting the DNA damage and inducing poly-ADP-ribosylation dependent chromatin relaxation and recruitment of repair proteins. Catalytic PARP inhibitors are used as anticancer drugs especially in the case of tumors arising from sensitizing mutations. Recently, a study showed that Histone PARylation Factor (HPF1) forms a joint active site with PARP1/2. The interaction of HPF1 with PARP1/2 alters the automodification site from Aspartate, Glutamate to Serine, which has been shown to be a key ADP-ribosylation event in the context of DNA damage. Therefore disruption of PARP1/2-HPF1 interaction could be an alternative strategy for drug development to block the PARP1/2 activity. In this study, we describe a FRET based high-throughput screening assay to screen inhibitor libraries against PARP-HPF1 interaction. We optimized the conditions for FRET signal and verified the interaction by competing the FRET pair in multiple ways. The assay is robust and easy to automate. Validatory screening showed the robust performance of the assay, and we discovered two compounds, Dimethylacrylshikonin and Alkannin, with μM inhibition potency against PARP1/2-HPF1 interaction. The assay will facilitate the discovery of inhibitors against HPF1-PARP1/2 complex and to develop potentially new effective anticancer agents.","PeriodicalId":486943,"journal":{"name":"bioRxiv (Cold Spring Harbor Laboratory)","volume":"46 14","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991900","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 : 2023-11-14DOI: 10.1101/2023.11.13.566826
Filipe Sobreira Rodrigues, Tiago Monteiro, Asma Motiwala, Joseph J Paton
To behave adaptively, the brain must register temporal structure in the environment and use it to organize behavior. The dorsolateral striatum (DLS) integrates sensorimotor cortical input, and is necessary for accurate timing and structuring behavior in general. However, if DLS provides the basis for mapping temporal features in the environment to behavior, its activity should predict variation in that mapping. A reanalysis of DLS population activity in rats comparing the duration of two sequentially presented vibratory stimuli revealed a striking correspondence between neural activity and behavior. Varying vibration intensity of the second stimulus induced systematic biases in temporal judgments, and corresponding biases in multiple features of DLS activity, including population coding of time. In contrast, the same intensity manipulations applied to the first stimulus affected neither behavior nor neural activity. Furthermore, neuronal response profiles were best described as a continuum, arguing against hypotheses where categories of responses, e.g., ramping activity, selectively underpin temporal processing. These data represent important additional evidence that striatal population dynamics support the organization of behavior by mapping temporal information to action.
{"title":"Dorsolateral striatum encodes a temporal basis for the organization of behavior","authors":"Filipe Sobreira Rodrigues, Tiago Monteiro, Asma Motiwala, Joseph J Paton","doi":"10.1101/2023.11.13.566826","DOIUrl":"https://doi.org/10.1101/2023.11.13.566826","url":null,"abstract":"To behave adaptively, the brain must register temporal structure in the environment and use it to organize behavior. The dorsolateral striatum (DLS) integrates sensorimotor cortical input, and is necessary for accurate timing and structuring behavior in general. However, if DLS provides the basis for mapping temporal features in the environment to behavior, its activity should predict variation in that mapping. A reanalysis of DLS population activity in rats comparing the duration of two sequentially presented vibratory stimuli revealed a striking correspondence between neural activity and behavior. Varying vibration intensity of the second stimulus induced systematic biases in temporal judgments, and corresponding biases in multiple features of DLS activity, including population coding of time. In contrast, the same intensity manipulations applied to the first stimulus affected neither behavior nor neural activity. Furthermore, neuronal response profiles were best described as a continuum, arguing against hypotheses where categories of responses, e.g., ramping activity, selectively underpin temporal processing. These data represent important additional evidence that striatal population dynamics support the organization of behavior by mapping temporal information to action.","PeriodicalId":486943,"journal":{"name":"bioRxiv (Cold Spring Harbor Laboratory)","volume":"4 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991990","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 : 2023-11-14DOI: 10.1101/2023.11.10.566398
Ines Alexandre Machado dos Santos, Katherine Snell, Rob van Bemmelen, Borge Moe, Kasper Thorup
Steep declines in Arctic skua populations have been reported during the last half of the 20th century in the southern extent of their breeding range. We used 24 years of available ringing and re-encounter data from the Faroe Islands, North Atlantic, to determine if patterns in survival probabilities can be explained by large scale climatic events. Having first determined the migratory phenology and wintering regions, we tested the North Atlantic Oscillation (NAO) index during breeding and Oceanic Niño index (ONI) during the non-breeding period within a capture-mark-recapture framework to model direct and time-lagged effects of the environment on annual survival. We found differential effects in the two age-classes examined: young and adults. Overall, three models were equally supported. We found strong support for a substantial decrease in adult annual survival over the study period, from ca. 0.93 probability of survival in 1985 to ca. 0.77 in 2008, and support for a decrease in young survival over the duration of the study period. Furthermore, we found support for increased chick survival following an El Niño winter. We suggest this reflects a potential carry-over effect of El Niño conditions positively impacting the performance of the parents in the subsequent breeding season, leading to improved chick survival prospects. The negative trend of adult survival cannot be attributed to the oceanic climate oscillations tested here; however, this result may account for the substantial population declines observed during the last decades.
{"title":"Wintering, rather than breeding, oceanic conditions contribute to declining survival in a long-distance migratory seabird","authors":"Ines Alexandre Machado dos Santos, Katherine Snell, Rob van Bemmelen, Borge Moe, Kasper Thorup","doi":"10.1101/2023.11.10.566398","DOIUrl":"https://doi.org/10.1101/2023.11.10.566398","url":null,"abstract":"Steep declines in Arctic skua populations have been reported during the last half of the 20th century in the southern extent of their breeding range. We used 24 years of available ringing and re-encounter data from the Faroe Islands, North Atlantic, to determine if patterns in survival probabilities can be explained by large scale climatic events. Having first determined the migratory phenology and wintering regions, we tested the North Atlantic Oscillation (NAO) index during breeding and Oceanic Niño index (ONI) during the non-breeding period within a capture-mark-recapture framework to model direct and time-lagged effects of the environment on annual survival. We found differential effects in the two age-classes examined: young and adults. Overall, three models were equally supported. We found strong support for a substantial decrease in adult annual survival over the study period, from ca. 0.93 probability of survival in 1985 to ca. 0.77 in 2008, and support for a decrease in young survival over the duration of the study period. Furthermore, we found support for increased chick survival following an El Niño winter. We suggest this reflects a potential carry-over effect of El Niño conditions positively impacting the performance of the parents in the subsequent breeding season, leading to improved chick survival prospects. The negative trend of adult survival cannot be attributed to the oceanic climate oscillations tested here; however, this result may account for the substantial population declines observed during the last decades.","PeriodicalId":486943,"journal":{"name":"bioRxiv (Cold Spring Harbor Laboratory)","volume":"39 21","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134992481","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 : 2023-11-14DOI: 10.1101/2023.11.10.566513
Ivan Pokrovac, Nicolas Rohner, Wesley C Warren, Zeljka Pezer
Copy number variation is a common contributor to phenotypic diversity, yet its involvement in ecological adaptation is not easily discerned. Instances of parallelly evolving populations of the same species in a similar environment marked by strong selective pressures present opportunities to study the role of copy number variants (CNVs) in adaptation. By identifying CNVs that repeatedly occur in independent populations of the derived ecotype and are not (or are rarely) present in the populations of the ancestral ecotype, the association of such CNVs with adaptation to the novel environment can be inferred. We used this paradigm to identify CNVs associated with recurrent adaptation of the Mexican tetra (Astyanax mexicanus) to cave environment. Using a read-depth approach, we detected CNVs from previously re-sequenced genomes of 44 individuals belonging to two ancestral surface and three derived cave populations. We identified 102 genes and 292 genomic regions that repeatedly diverge in copy number between the two ecotypes and occupy 0.8% of the reference genome. Functional analysis revealed their association with processes previously recognized to be relevant for adaptation, such as vision, immunity, oxygen consumption, metabolism, and neural function and we propose that these variants have been selected for in the cave or surface waters. The majority of the ecotype-divergent CNVs are multiallelic and display copy-number increases in cave fish compared to surface fish. Our findings suggest that multiallelic CNVs - including gene duplications, and divergence in copy number provide a fast route to produce novel phenotypes associated with adaptation to subterranean life.
{"title":"The prevalence of copy number increase at multiallelic CNVs associated with cave colonization","authors":"Ivan Pokrovac, Nicolas Rohner, Wesley C Warren, Zeljka Pezer","doi":"10.1101/2023.11.10.566513","DOIUrl":"https://doi.org/10.1101/2023.11.10.566513","url":null,"abstract":"Copy number variation is a common contributor to phenotypic diversity, yet its involvement in ecological adaptation is not easily discerned. Instances of parallelly evolving populations of the same species in a similar environment marked by strong selective pressures present opportunities to study the role of copy number variants (CNVs) in adaptation. By identifying CNVs that repeatedly occur in independent populations of the derived ecotype and are not (or are rarely) present in the populations of the ancestral ecotype, the association of such CNVs with adaptation to the novel environment can be inferred. We used this paradigm to identify CNVs associated with recurrent adaptation of the Mexican tetra (Astyanax mexicanus) to cave environment. Using a read-depth approach, we detected CNVs from previously re-sequenced genomes of 44 individuals belonging to two ancestral surface and three derived cave populations. We identified 102 genes and 292 genomic regions that repeatedly diverge in copy number between the two ecotypes and occupy 0.8% of the reference genome. Functional analysis revealed their association with processes previously recognized to be relevant for adaptation, such as vision, immunity, oxygen consumption, metabolism, and neural function and we propose that these variants have been selected for in the cave or surface waters. The majority of the ecotype-divergent CNVs are multiallelic and display copy-number increases in cave fish compared to surface fish. Our findings suggest that multiallelic CNVs - including gene duplications, and divergence in copy number provide a fast route to produce novel phenotypes associated with adaptation to subterranean life.","PeriodicalId":486943,"journal":{"name":"bioRxiv (Cold Spring Harbor Laboratory)","volume":"40 8","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134992524","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}
Hyperinflammation is the hallmark of Kaposi's sarcoma (KS), the most common cancer in AIDS patients caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection. However, the role and mechanism of induction of inflammation in KS remain unclear. In a screening for inhibitors of KSHV-induced oncogenesis, over half of the identified candidates were anti-inflammatory agents including dexamethasone functions by activating glucocorticoid receptor (GR) signaling. Here, we examined the mechanism mediating KSHV-induced inflammation. We found that numerous inflammatory pathways were activated in KSHV-transformed cells. Particularly, interleukin-1 alpha (IL-1α) and IL-1 receptor antagonist (IL-1Ra) from the IL-1 family were the most induced and suppressed cytokines, respectively. We found that KSHV miRNAs mediated IL-1α induction while both miRNAs and vFLIP mediated IL-1Ra suppression. Furthermore, GR signaling was inhibited in KSHV-transformed cells, which was mediated by vFLIP and vCyclin. Dexamethasone treatment activated GR signaling, and inhibited cell proliferation and colony formation in soft agar of KSHV-transformed cells but had a minimal effect on matched primary cells. Consequently, dexamethasone suppressed the initiation and growth of KSHV-induced tumors in mice. Mechanistically, dexamethasone suppressed IL-1α but induced IL-1Ra expression. Treatment with recombinant IL-1α protein rescued the inhibitory effect of dexamethasone while overexpression of IL-1Ra caused a weak growth inhibition of KSHV-transformed cells. Furthermore, dexamethasone induced IκBα expression resulting in inhibition of NF-kB pathway and IL-1α expression. These results reveal an important role of IL-1 pathway in KSHV-induced inflammation and oncogenesis, which can be inhibited by dexamethasone-activated GR signaling, and identify IL-1-mediated inflammation as a potential therapeutic target for KSHV-induced malignancies.
卡波西肉瘤(KS)是艾滋病患者中最常见的癌症，由卡波西肉瘤相关疱疹病毒(KSHV)感染引起。然而，炎症诱导在KS中的作用和机制尚不清楚。在筛选kshv诱导的肿瘤发生抑制剂时，超过一半的候选药物是抗炎药，包括通过激活糖皮质激素受体(GR)信号来发挥地塞米松作用的药物。在这里，我们研究了介导kshv诱导炎症的机制。我们发现，在kshv转化的细胞中，许多炎症途径被激活。特别是，来自IL-1家族的白细胞介素-1α (IL-1α)和IL-1受体拮抗剂(IL-1Ra)分别是诱导和抑制最多的细胞因子。我们发现KSHV miRNAs介导IL-1α诱导，而miRNAs和vFLIP介导IL-1Ra抑制。此外，在kshv转化的细胞中，vFLIP和vCyclin介导的GR信号被抑制。地塞米松处理激活了GR信号，抑制了kshv转化细胞在软琼脂中的增殖和集落形成，但对匹配的原代细胞影响很小。因此，地塞米松抑制kshv诱导的小鼠肿瘤的发生和生长。地塞米松抑制IL-1α，诱导IL-1Ra表达。重组IL-1α蛋白处理可恢复地塞米松的抑制作用，而过表达IL-1Ra对kshv转化细胞的生长抑制作用较弱。此外，地塞米松诱导i - κ b α表达，抑制NF-kB通路和IL-1α表达。这些结果揭示了IL-1通路在kshv诱导的炎症和肿瘤发生中的重要作用，可以被地塞米松激活的GR信号抑制，并确定IL-1介导的炎症是kshv诱导的恶性肿瘤的潜在治疗靶点。
{"title":"Activation of glucocorticoid receptor signaling inhibits KSHV-induced inflammation and tumorigenesis","authors":"Luping Chen, Ling Ding, Xian Wang, Yufei Huang, Shou-Jiang Gao","doi":"10.1101/2023.11.10.566578","DOIUrl":"https://doi.org/10.1101/2023.11.10.566578","url":null,"abstract":"Hyperinflammation is the hallmark of Kaposi's sarcoma (KS), the most common cancer in AIDS patients caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection. However, the role and mechanism of induction of inflammation in KS remain unclear. In a screening for inhibitors of KSHV-induced oncogenesis, over half of the identified candidates were anti-inflammatory agents including dexamethasone functions by activating glucocorticoid receptor (GR) signaling. Here, we examined the mechanism mediating KSHV-induced inflammation. We found that numerous inflammatory pathways were activated in KSHV-transformed cells. Particularly, interleukin-1 alpha (IL-1α) and IL-1 receptor antagonist (IL-1Ra) from the IL-1 family were the most induced and suppressed cytokines, respectively. We found that KSHV miRNAs mediated IL-1α induction while both miRNAs and vFLIP mediated IL-1Ra suppression. Furthermore, GR signaling was inhibited in KSHV-transformed cells, which was mediated by vFLIP and vCyclin. Dexamethasone treatment activated GR signaling, and inhibited cell proliferation and colony formation in soft agar of KSHV-transformed cells but had a minimal effect on matched primary cells. Consequently, dexamethasone suppressed the initiation and growth of KSHV-induced tumors in mice. Mechanistically, dexamethasone suppressed IL-1α but induced IL-1Ra expression. Treatment with recombinant IL-1α protein rescued the inhibitory effect of dexamethasone while overexpression of IL-1Ra caused a weak growth inhibition of KSHV-transformed cells. Furthermore, dexamethasone induced IκBα expression resulting in inhibition of NF-kB pathway and IL-1α expression. These results reveal an important role of IL-1 pathway in KSHV-induced inflammation and oncogenesis, which can be inhibited by dexamethasone-activated GR signaling, and identify IL-1-mediated inflammation as a potential therapeutic target for KSHV-induced malignancies.","PeriodicalId":486943,"journal":{"name":"bioRxiv (Cold Spring Harbor Laboratory)","volume":"24 11","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134992849","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 : 2023-11-14DOI: 10.1101/2023.11.13.565999
Luis M. Silva, Gwendoline Acerbi, Marine Amann, Jacob C. Koella
The microbiota of mosquitoes influences many aspects of their biology, including developmental processes, mating and sexual reproduction, immune functions, and refractoriness to pathogens. Here, we considered their role in resistance against insecticides. In particular, we assessed how larval infection of a permethrin-resistant and a sensitive colony of Anopheles gambiae by four strains belonging to three different Pseudomonas species affects several life history traits and the impact of the insecticide on the mortality of adults. Our data showed that all four Pseudomonas species persisted in adults until death. The bacteria increased the likelihood that mosquitoes survived 24 hours after exposure to permethrin by up to two-fold. The impact of the bacteria depended on the bacterial species and the mosquito colony: in the resistant colony, all bacteria increased survival by about 2-fold, while in the sensitive colony, only two of the four species increased survival. The benefit with regard to insecticide resistance came with little to no impact on the other traits (i.e., larval mortality, developmental time and adult longevity). Altogether, our results highlight the importance of considering environmental microbial exposure and mosquito microbial communities in epidemiological and vector-control studies, while also suggesting a possible role for Pseudomonas spp. as a symbiont in A. gambiae .
{"title":"Exposure to<i>Pseudomonas spp.</i>increases<i>Anopheles gambiae</i>insecticide resistance in a population-dependent manner","authors":"Luis M. Silva, Gwendoline Acerbi, Marine Amann, Jacob C. Koella","doi":"10.1101/2023.11.13.565999","DOIUrl":"https://doi.org/10.1101/2023.11.13.565999","url":null,"abstract":"The microbiota of mosquitoes influences many aspects of their biology, including developmental processes, mating and sexual reproduction, immune functions, and refractoriness to pathogens. Here, we considered their role in resistance against insecticides. In particular, we assessed how larval infection of a permethrin-resistant and a sensitive colony of Anopheles gambiae by four strains belonging to three different Pseudomonas species affects several life history traits and the impact of the insecticide on the mortality of adults. Our data showed that all four Pseudomonas species persisted in adults until death. The bacteria increased the likelihood that mosquitoes survived 24 hours after exposure to permethrin by up to two-fold. The impact of the bacteria depended on the bacterial species and the mosquito colony: in the resistant colony, all bacteria increased survival by about 2-fold, while in the sensitive colony, only two of the four species increased survival. The benefit with regard to insecticide resistance came with little to no impact on the other traits (i.e., larval mortality, developmental time and adult longevity). Altogether, our results highlight the importance of considering environmental microbial exposure and mosquito microbial communities in epidemiological and vector-control studies, while also suggesting a possible role for Pseudomonas spp. as a symbiont in A. gambiae .","PeriodicalId":486943,"journal":{"name":"bioRxiv (Cold Spring Harbor Laboratory)","volume":"45 9","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134900923","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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