Probing protein flexibility reveals a mechanism for selective promiscuity.

Elife. 2017 Apr 22;6:

Authors: Pabon NA, Camacho CJ

Abstract
Many eukaryotic regulatory proteins adopt distinct bound and unbound conformations, and use this structural flexibility to bind specifically to multiple partners. However, we lack an understanding of how an interface can select some ligands, but not others. Here, we present a molecular dynamics approach to identify and quantitatively evaluate the interactions responsible for this selective promiscuity. We apply this approach to the anti-cancer target PD-1 and its ligands PD-L1 and PD-L2. We discover that while unbound PD-1 exhibits a hard-to-drug hydrophilic interface, conserved specific triggers encoded in the cognate ligands activate a promiscuous binding pathway that reveals a flexible hydrophobic binding cavity. Specificity is then established by additional contacts that stabilize the PD-1 cavity into distinct bound-like modes. Collectively, our studies provide insight into the structural basis and evolution of multiple binding partners, and also suggest a biophysical approach to exploit innate binding pathways to drug seemingly undruggable targets.

PMID: 28432789 [PubMed - as supplied by publisher]

Genome characteristics of the proteorhodopsin-containing marine flavobacterium Polaribacter dokdonensis DSW-5.

J Microbiol. 2017 Apr 22;:

Authors: Yoon K, Song JY, Kwak MJ, Kwon SK, Kim JF

Abstract
Bacteria in the genus Polaribacter, belonging to the family Flavobacteriaceae, are typically isolated from marine environments. Polaribacter dokdonensis DSW-5, the type strain of the species, is a Gram-negative bacterium isolated from the East Sea of Korea. Whole genome shotgun sequencing was performed with the HiSeq 2000 platform and paired-end reads were generated at 188-fold coverage. The sequencing reads were assembled into two contigs with a total length of 3.08 Mb. The genome sequences of DSW-5 contain 2,776 proteincoding sequences and 41 RNA genes. Comparison of average nucleotide identities among six available Polaribacteria genomes including DSW-5 suggested that the DSW-5 genome is most similar to that of Polaribacter sp. MED152, which is a proteorhodopsin-containing marine bacterium. A phylogenomic analysis of the six Polaribacter strains and 245 Flavobacteriaceae bacteria confirmed a close relationship of the genus Polaribacter with Tenacibaculum and Kordia. DSW-5's genome has a gene encoding proteorhodopsin and genes encoding 85 enzymes belonging to carbohydrate-active enzyme families and involved in polysaccharide degradation, which may play important roles in energy metabolism of the bacterium in the marine ecosystem. With genes for 238 CAZymes and 203 peptidases, DSW-5 has a relatively high number of degrading enzymes for its genome size suggesting its characteristics as a free-living marine heterotroph.

PMID: 28432541 [PubMed - as supplied by publisher]

Systematic Synergy of Glucose and GLP-1 to Stimulate Insulin Secretion Revealed by Quantitative Phosphoproteomics.

Sci Rep. 2017 Apr 21;7(1):1018

Authors: Tang JS, Li QR, Li JM, Wu JR, Zeng R

Abstract
GLP-1 synergizes with glucose in regulating pancreatic β-cell function, including facilitating β-cell survival and insulin secretion. Though it has been widely accepted that phosphorylation is extremely important in regulating β-cell functions, our knowledge to the global mechanism is still limited. Here we performed a quantitative phosphoproteomics study to systematically present the synergistic regulation of INS-1E cell phosphoproteome mediated by glucose and GLP-1. We generated the largest pancreatic β-cell phosphoproteome by identifying 25,327 accurately localized phosphorylation sites on 5,389 proteins. Our results discovered several novel kinases regulated by glucose, GLP-1 or their synergism, and some of these kinases might act as downstream molecules of GLP-1 mediated PKA signaling cascade. A few phosphosites were regulated by both GLP-1 and glucose alone, and these target proteins were highly related to their biological function on pancreatic β-cells. Finally, we found glucose and GLP-1 executed their synergistic effect at multiple levels, especially at pathway level. Both GLP-1 and glucose participated in regulating every single step of the secretion pathway, and systematically synergized their effects in inducing insulin secretion.

PMID: 28432305 [PubMed - in process]

Quantitative Imaging of Cerebral Thromboemboli In Vivo: The Effects of Tissue-Type Plasminogen Activator.

Stroke. 2017 Apr 21;:

Authors: Kim DE, Kim JY, Schellingerhout D, Ryu JH, Lee SK, Jeon S, Lee JS, Kim J, Jang HJ, Park JE, Kim EJ, Kwon IC, Ahn CH, Nahrendorf M, Kim K

Abstract
BACKGROUND AND PURPOSE: Quantitative imaging for the noninvasive assessment of thrombolysis is needed to advance basic and clinical thrombosis-related research and tailor tissue-type plasminogen activator (tPA) treatment for stroke patients. We quantified the evolution of cerebral thromboemboli using fibrin-targeted glycol chitosan-coated gold nanoparticles and microcomputed tomography, with/without tPA therapy.
METHODS: We injected thrombi into the distal internal carotid artery in mice (n=50). Fifty-five minutes later, we injected fibrin-targeted glycol chitosan-coated gold nanoparticles, and 5 minutes after that, we treated animals with tPA or not (25 mg/kg). We acquired serial microcomputed tomography images for 24 hours posttreatment.
RESULTS: Thrombus burden at baseline was 784×10(3)±59×10(3) μm(2) for the tPA group (n=42) and 655×10(3)±103×10(3) μm(2) for the saline group (n=8; P=0.37). Thrombus shrinkage began at 0.5 to 1 hour after tPA therapy, with a maximum initial rate of change at 4603±957 μm(2)/min. The rate of change lowered to ≈61% level of the initial in hours 1 to 2, followed by ≈29% and ≈1% in hours 2 to 3 and 3 to 24, respectively. Thus, 85% of total thrombolysis over 24 hours (≈500 μm(2), equivalent to 64% of the baseline thrombus burden) occurred within the first 3 hours of treatment. Thrombus burden at 24 hours could be predicted at around 1.5 to 2 hours. Saline treatment was not associated with significant changes in the thrombus burden. Infarct size was smaller in the tPA group versus saline group (18.1±2.3 versus 45.8±3.3 mm(2); P<0.01). Infarct size correlated to final thrombus burden (r=0.71; P<0.01). Time to thrombolysis, completeness of thrombolysis, and tPA therapy were independent predictors of infarct size.
CONCLUSIONS: Thromboembolic burden and the efficacy of tPA therapy can be assessed serially, noninvasively, and quantitatively using high-resolution microcomputed tomography and a fibrin-binding nanoparticle imaging agent.

PMID: 28432262 [PubMed - as supplied by publisher]

N-terminal proteomics assisted profiling of the unexplored translation initiation landscape in Arabidopsis thaliana.

Mol Cell Proteomics. 2017 Apr 21;:

Authors: Willems P, Ndah E, Jonckheere V, Stael S, Sticker A, Martens L, Van Breusegem F, Gevaert K, Van Damme P

Abstract
Proteogenomics is an emerging research field yet lacking a uniform method of analysis. Proteogenomic studies in which N-terminal proteomics and ribosome profiling are combined, suggest that a high number of protein start sites are currently missing in genome annotations. We constructed a proteogenomic pipeline specific for the analysis of N-terminal proteomics data, with the aim of discovering novel translational start sites outside annotated protein coding regions. In summary, unidentified MS/MS spectra were matched to a specific N-terminal peptide library encompassing protein N-termini encoded in the Arabidopsis thaliana genome. After a stringent false discovery rate filtering, 157 protein N-termini compliant with N-terminal methionine excision specificity and indicative of translation initiation were found. These include N-terminal protein extensions and translation from transposable elements and pseudogenes. Gene prediction provided supporting protein-coding models for approximately half of the protein N-termini. Besides the prediction of functional domains (partially) contained within the newly predicted ORFs, further supporting evidence of translation was found in the recently released Araport11 genome re-annotation of Arabidopsis and computational translations of sequences stored in public repositories. Most interestingly, complementary evidence by ribosome profiling was found for 23 protein N-termini. Finally, by analyzing protein N-terminal peptides, an in silico analysis demonstrates the applicability of our N-terminal proteogenomics strategy in revealing protein-coding potential in species with well- and poorly-annotated genomes.

PMID: 28432195 [PubMed - as supplied by publisher]

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"systems biology"

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Whole genome sequencing of matched tumor, adjacent non-tumor tissues and corresponding normal blood samples of hepatocellular carcinoma patients revealed dynamic changes of the mutations profiles during hepatocarcinogenesis.

Oncotarget. 2017 Feb 17;:

Authors: Mao R, Liu J, Liu G, Jin S, Xue Q, Ma L, Fu Y, Zhao N, Xing J, Li L, Qiu Y, Lin B

Abstract
Hepatocellular carcinoma (HCC) has become the third most deadly disease worldwide and HBV is the major factor in Asia and Africa. We conducted 9 WGS (whole genome sequencing) analyses for matched samples of tumor, adjacent non-tumor tissues and normal blood samples of HCC patients from three HBV positive patients. We then validated the mutations identified in a larger cohort of 177 HCC patients. We found that the number of the unique somatic mutations (average of 59,136) in tumor samples is significantly less than that in adjacent non-tumor tissues (average 83, 633). We discovered that the TP53 R249S mutation occurred in 7.7% of the HCC patients, and it was significantly associated with poor diagnosis. In addition, we found that the L104P mutation in the VCX gene (Variable charge, X-linked) was absent in white blood cell samples, but present at 11.1% frequency in the adjacent tissues and increased to 14.6% in HCC tissues, suggesting that this mutation might be a tumor driver gene driving HCC carcinogenesis. Finally, we identified a TK1-RNU7 fusion, which would result in a deletion of 103 amino acids from its C-terminal. The frequencies of this fusion event decreased from the adjacent tissues (29.2%) to the tumors (16.7%), suggesting that a truncated thymidine Kinase1 (TK1) caused by the fusion event might be deleterious and be selected against during tumor progression. The three-way comparisons allow the identification of potential driver mutations of carcinogenesis. Furthermore, our dataset provides the research community a valuable dataset for identifying dynamic changes of mutation profiles and driver mutations for HCC.

PMID: 28412734 [PubMed - as supplied by publisher]

During yeast chronological aging resveratrol supplementation results in a short-lived phenotype Sir2-dependent.

Redox Biol. 2017 Apr 09;12:745-754

Authors: Orlandi I, Stamerra G, Strippoli M, Vai M

Abstract
Resveratrol (RSV) is a naturally occurring polyphenolic compound endowed with interesting biological properties/functions amongst which are its activity as an antioxidant and as Sirtuin activating compound towards SIRT1 in mammals. Sirtuins comprise a family of NAD(+)-dependent protein deacetylases that are involved in many physiological and pathological processes including aging and age-related diseases. These enzymes are conserved across species and SIRT1 is the closest mammalian orthologue of Sir2 of Saccharomyces cerevisiae. In the field of aging researches, it is well known that Sir2 is a positive regulator of replicative lifespan and, in this context, the RSV effects have been already examined. Here, we analyzed RSV effects during chronological aging, in which Sir2 acts as a negative regulator of chronological lifespan (CLS). Chronological aging refers to quiescent cells in stationary phase; these cells display a survival-based metabolism characterized by an increase in oxidative stress. We found that RSV supplementation at the onset of chronological aging, namely at the diauxic shift, increases oxidative stress and significantly reduces CLS. CLS reduction is dependent on Sir2 presence both in expired medium and in extreme Calorie Restriction. In addition, all data point to an enhancement of Sir2 activity, in particular Sir2-mediated deacetylation of the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase (Pck1). This leads to a reduction in the amount of the acetylated active form of Pck1, whose enzymatic activity is essential for gluconeogenesis and CLS extension.

PMID: 28412652 [PubMed - as supplied by publisher]

Phosphorylation of WHIRLY1 by CIPK14 shifts its localization and dual functions in Arabidopsis.

Mol Plant. 2017 Apr 12;:

Authors: Ren Y, Li Y, Jiang Y, Wu B, Miao Y

Abstract
Plastid-to-nucleus retrograde signaling is critical for normal growth and development in plants. The dual-function and dual-located ssDNA binding protein WHIRLY1 (WHY1) has been supposed to coordinate the retrograde signaling from plastids to the nucleus. However, the regulatory mechanism governing the functional switch of WHY1 for mediating plastid-to-nucleus retrograde signaling remains unknown. Here we report that the Calcineurin B-Like-Interacting Protein Kinase14 (CIPK14) interacts with and phosphorylates WHY1 in Arabidopsis. Phosphorylation of WHY1 results in increased accumulation in the nucleus and enhanced binding with the promoter of WRKY53, which encodes a key transcription factor regulating leaf senescence in Arabidopsis. Transgenic plants overexpressing CIPK14 showed increased nuclear isoform but decreased plastid isoform of WHY1, among which 95% transgenic lines showed the stay-green phenotype and 5% lines with variegated pale-green phenotype. Interestingly, the phenotypes of both types of transgenic plants could be recovered by overexpression of plastid-form WHY1. In contrast, knockdown of CIPK14 caused early senescence and even seedling-lethal phenotypes along with elevated expression of the senescence-related genes such as WRKY53, SAG12 and NDHF but decreased expression of MER11, RAD50 and POR genes, which could be rescued by overexpression of CIPK14 but neither by overexpressing the plastid-form or nuclear-form WHY1, whereas the stay-green plants overexpressing CIPK14 showed reduced expression of WRKY53, SAG12, NDHF and large plastid rRNA. Consistently, the accumulation of nuclear-form WHY1 was significantly reduced in the CIPK14 knockdown lines, resulting in a low ratio of nuclear/plastid-form WHY1. Taken together, our results demonstrates that CIPK14 regulates the phosphorylation and organelle distributions of WHY1, which may function as a cellular switch between leaf senescence and plastid development for coordinating the intercellular signaling in Arabidopsis.

PMID: 28412544 [PubMed - as supplied by publisher]

Endotoxin induced TLR4 signaling downregulates CYP19A1 expression through CEBPB in buffalo granulosa cells.

Toxicol In Vitro. 2017 Apr 13;:

Authors: Rao Y, Ravinder, Singh D

Abstract
Estrogen is essential for growth and development of ovarian follicles. Infections associated with E. coli or Endotoxin (LPS) suppress estradiol production by the downregulation of CYP19A1 expression. However, the molecular mechanism of its down regulation is not yet known. To elucidate the molecular mechanisms of LPS-mediated downregulation of CYP19A1 gene expression, we studied the effect of LPS and TLR4 signaling pathway inhibitor (OxPAPC, OxPAPC-Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine) on CYP19A1 expression, and expression of CEBPB and CEBPB binding on CYP19A1 proximal promoter (CYP19A1 PII) in buffalo granulosa cells in vitro. The results showed that LPS (1μg/ml) significantly declined the expression of CYP19A1 gene. In further experiments, inhibitor studies confirmed the involvement of TLR4 in LPS induced CYP19A1 gene down regulation in buffalo granulosa cells. LPS promoted higher levels of CEBPB at cellular and nuclear level in granulosa cells. Chromatin immunoprecipitation results showed, that LPS induces higher amount of CEBPB binding on the CYP19A1 PII. Further, TLR4 inhibitor attenuated the LPS induced implications. In conclusion, our results demonstrated that CEBPB could be a potential regulator for LPS mediated downregulation of CYP19A1 and decline of 17-beta estradiol levels in buffalo granulosa cells.

PMID: 28412504 [PubMed - as supplied by publisher]

RNA-Binding Proteins Revisited - The Emerging Arabidopsis mRNA Interactome.

Trends Plant Sci. 2017 Apr 12;:

Authors: Köster T, Marondedze C, Meyer K, Staiger D

Abstract
RNA-protein interaction is an important checkpoint to tune gene expression at the RNA level. Global identification of proteins binding in vivo to mRNA has been possible through interactome capture - where proteins are fixed to target RNAs by UV crosslinking and purified through affinity capture of polyadenylated RNA. In Arabidopsis over 500 RNA-binding proteins (RBPs) enriched in UV-crosslinked samples have been identified. As in mammals and yeast, the mRNA interactomes came with a few surprises. For example, a plethora of the proteins caught on RNA had not previously been linked to RNA-mediated processes, for example proteins of intermediary metabolism. Thus, the studies provide unprecedented insights into the composition of the mRNA interactome, highlighting the complexity of RNA-mediated processes.

PMID: 28412036 [PubMed - as supplied by publisher]

Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-resistant Prostate Cancer.

Cancer Discov. 2017 Apr 14;:

Authors: Zou M, Toivanen R, Mitrofanova A, Floc'h N, Hayati S, Sun Y, Le Magnen C, Chester D, Mostaghel EA, Califano A, Rubin MA, Shen MM, Abate-Shen C

Abstract
Current treatments for castration-resistant prostate cancer (CPRC) that target androgen receptor (AR) signaling improve patient survival, yet ultimately fail. Here we provide novel insights into treatment response for the anti-androgen abiraterone by analyses of a genetically-engineered mouse model (GEMM) with combined inactivation of Trp53 and Pten, which are frequently co-mutated in human CRPC. These NPp53 mice fail to respond to abiraterone, and display accelerated progression to tumors resembling treatment-related CRPC with neuroendocrine differentiation (CRPC-NE) in humans. Cross-species computational analyses identify master regulators of adverse response that are conserved with human CRPC-NE, including the neural differentiation factor SOX11, which promotes neuroendocrine differentiation in cells derived from NPp53 tumors. Furthermore, abiraterone-treated NPp53 prostate tumors contain regions of focal and/or overt neuroendocrine differentiation, distinguished by their proliferative potential. Notably, lineage-tracing in vivo provides definitive and quantitative evidence that focal and overt neuroendocrine regions arise by transdifferentiation of luminal adenocarcinoma cells. These findings underscore principal roles for TP53 and PTEN inactivation in abiraterone resistance and progression from adenocarcinoma to CRPC-NE by transdifferentiation.

PMID: 28411207 [PubMed - as supplied by publisher]

M3 muscarinic acetylcholine receptor facilitates the endocytosis of mu opioid receptor mediated by morphine independently of the formation of heteromeric complexes.

Cell Signal. 2017 Apr 11;:

Authors: Lopez-Gimenez JF, Alvarez-Curto E, Milligan G

Abstract
Morphine inefficiency to induce the internalization of mu opioid (MOP) receptors observed in numerous experimental models constitutes a paradigm of G-protein coupled receptor (GPCR) functional selectivity. We recently described that activation of Gαq/11 proteins through 5-HT2A serotonin receptors co-expressed in the same cells facilitates MOP receptor endocytosis promoted by morphine. In order to explore whether a different Gαq/11 coupled GPCR would emulate this effect, a double stable Flp-In T-REx HEK293 cell line permanently expressing MOP-YFP receptors along with FLAG-M3-Cerulean receptors expressed in an inducible manner was generated. Fluorescence microscopy examination of these cells revealed a co-distribution of both receptors mainly compartmentalized in plasma membrane. Concurrent stimulation with carbachol and morphine promoted MOP receptor internalization, desensitization and down-regulation and this facilitation was not dependent on PKC activation. Co-immunoprecipitation experiments demonstrated that FLAG-M3-Cerulean/MOP-YFP receptors interact forming heteromeric complexes in a time depending manner, i.e. the strongest interaction was detected after 96h of FLAG-M3-Cerulean induced expression. Under these experimental conditions, treatment of cells with carbachol plus morphine resulted in the internalization of both receptors within separated endocytic vesicles as visualized by confocal microscopy. This trafficking segregation observed for FLAG-M3-Cerulean and MOP-YFP receptors upon agonist stimulation suggests that this protein-protein interaction presents temporal and dynamic properties. Moreover, MOP-YFP receptor internalization facilitated by FLAG-M3-Cerulean receptors is independent of the constitution of heteromeric complexes.

PMID: 28411124 [PubMed - as supplied by publisher]

iPSCORE: A Resource of 222 iPSC Lines Enabling Functional Characterization of Genetic Variation across a Variety of Cell Types.

Stem Cell Reports. 2017 Apr 11;8(4):1086-1100

Authors: Panopoulos AD, D'Antonio M, Benaglio P, Williams R, Hashem SI, Schuldt BM, DeBoever C, Arias AD, Garcia M, Nelson BC, Harismendy O, Jakubosky DA, Donovan MKR, Greenwald WW, Farnam K, Cook M, Borja V, Miller CA, Grinstein JD, Drees F, Okubo J, Diffenderfer KE, Hishida Y, Modesto V, Dargitz CT, Feiring R, Zhao C, Aguirre A, McGarry TJ, Matsui H, Li H, Reyna J, Rao F, O'Connor DT, Yeo GW, Evans SM, Chi NC, Jepsen K, Nariai N, Müller FJ, Goldstein LSB, Izpisua Belmonte JC, Adler E, Loring JF, Berggren WT, D'Antonio-Chronowska A, Smith EN, Frazer KA

Abstract
Large-scale collections of induced pluripotent stem cells (iPSCs) could serve as powerful model systems for examining how genetic variation affects biology and disease. Here we describe the iPSCORE resource: a collection of systematically derived and characterized iPSC lines from 222 ethnically diverse individuals that allows for both familial and association-based genetic studies. iPSCORE lines are pluripotent with high genomic integrity (no or low numbers of somatic copy-number variants) as determined using high-throughput RNA-sequencing and genotyping arrays, respectively. Using iPSCs from a family of individuals, we show that iPSC-derived cardiomyocytes demonstrate gene expression patterns that cluster by genetic background, and can be used to examine variants associated with physiological and disease phenotypes. The iPSCORE collection contains representative individuals for risk and non-risk alleles for 95% of SNPs associated with human phenotypes through genome-wide association studies. Our study demonstrates the utility of iPSCORE for examining how genetic variants influence molecular and physiological traits in iPSCs and derived cell lines.

PMID: 28410642 [PubMed - in process]

Natural selection drove metabolic specialization of the chromatophore in Paulinella chromatophora.

BMC Evol Biol. 2017 Apr 14;17(1):99

Authors: Valadez-Cano C, Olivares-Hernández R, Resendis-Antonio O, DeLuna A, Delaye L

Abstract
BACKGROUND: Genome degradation of host-restricted mutualistic endosymbionts has been attributed to inactivating mutations and genetic drift while genes coding for host-relevant functions are conserved by purifying selection. Unlike their free-living relatives, the metabolism of mutualistic endosymbionts and endosymbiont-originated organelles is specialized in the production of metabolites which are released to the host. This specialization suggests that natural selection crafted these metabolic adaptations. In this work, we analyzed the evolution of the metabolism of the chromatophore of Paulinella chromatophora by in silico modeling. We asked whether genome reduction is driven by metabolic engineering strategies resulted from the interaction with the host. As its widely known, the loss of enzyme coding genes leads to metabolic network restructuring sometimes improving the production rates. In this case, the production rate of reduced-carbon in the metabolism of the chromatophore.
RESULTS: We reconstructed the metabolic networks of the chromatophore of P. chromatophora CCAC 0185 and a close free-living relative, the cyanobacterium Synechococcus sp. WH 5701. We found that the evolution of free-living to host-restricted lifestyle rendered a fragile metabolic network where >80% of genes in the chromatophore are essential for metabolic functionality. Despite the lack of experimental information, the metabolic reconstruction of the chromatophore suggests that the host provides several metabolites to the endosymbiont. By using these metabolites as intracellular conditions, in silico simulations of genome evolution by gene lose recover with 77% accuracy the actual metabolic gene content of the chromatophore. Also, the metabolic model of the chromatophore allowed us to predict by flux balance analysis a maximum rate of reduced-carbon released by the endosymbiont to the host. By inspecting the central metabolism of the chromatophore and the free-living cyanobacteria we found that by improvements in the gluconeogenic pathway the metabolism of the endosymbiont uses more efficiently the carbon source for reduced-carbon production. In addition, our in silico simulations of the evolutionary process leading to the reduced metabolic network of the chromatophore showed that the predicted rate of released reduced-carbon is obtained in less than 5% of the times under a process guided by random gene deletion and genetic drift. We interpret previous findings as evidence that natural selection at holobiont level shaped the rate at which reduced-carbon is exported to the host. Finally, our model also predicts that the ABC phosphate transporter (pstSACB) which is conserved in the genome of the chromatophore of P. chromatophora strain CCAC 0185 is a necessary component to release reduced-carbon molecules to the host.
CONCLUSION: Our evolutionary analysis suggests that in the case of Paulinella chromatophora natural selection at the holobiont level played a prominent role in shaping the metabolic specialization of the chromatophore. We propose that natural selection acted as a "metabolic engineer" by favoring metabolic restructurings that led to an increased release of reduced-carbon to the host.

PMID: 28410570 [PubMed - in process]

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