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DOE OSTI2020

Structural snapshots of human DNA polymerase μ engaged on a DNA double-strand break

Genomic integrity is threatened by cytotoxic DNA double-strand breaks (DSBs), which must be resolved efficiently to prevent sequence loss, chromosomal rearrangements/translocations, or cell death. Polymerase μ (Polμ) participates in DSB repair via the nonhomologous end-joining (NHEJ) pathway, by filling small sequence gaps in broken ends to create substrates ultimately ligatable by DNA Ligase IV. Here we present structures of human Polμ engaging a DSB substrate. Synapsis is mediated solely by Polμ, facilitated by single-nucleotide homology at the break site, wherein both ends of the discontinuous template strand are stabilized by a hydrogen bonding network. The active site in the quaternary Pol μ complex is poised for catalysis and nucleotide incoporation proceeds in crystallo. These structures demonstrate that Polμ may address complementary DSB substrates during NHEJ in a manner indistinguishable from single-strand breaks.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

A monomeric mycobacteriophage immunity repressor utilizes two domains to recognize an asymmetric DNA sequence

Regulation of bacteriophage gene expression involves repressor proteins that bind and downregulate early lytic promoters. A large group of mycobacteriophages code for repressors that are unusual in also terminating transcription elongation at numerous binding sites (stoperators) distributed across the phage genome. Here we provide the X-ray crystal structure of a mycobacteriophage immunity repressor bound to DNA, which reveals the binding of a monomer to an asymmetric DNA sequence using two independent DNA binding domains. The structure is supported by small-angle X-ray scattering, DNA binding, molecular dynamics, and in vivo immunity assays. We propose a model for how dual DNA binding domains facilitate regulation of both transcription initiation and elongation, while enabling evolution of other superinfection immune specificities.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Mechanistic investigation of SARS-CoV-2 main protease to accelerate design of covalent inhibitors

Targeted covalent inhibition represents one possible strategy to block the function of SARS-CoV-2 Main Protease (M PRO ), an enzyme that plays a critical role in the replication of the novel SARS-CoV-2. Toward the design of covalent inhibitors, we built a covalent inhibitor dataset using deep learning models followed by high throughput virtual screening of these candidates against M PRO . Two top-ranking inhibitors were selected for mechanistic investigations—one with an activated ester warhead that has a piperazine core and the other with an acrylamide warhead. Specifically, we performed a detailed analysis of the free energetics of covalent inhibition by hybrid quantum mechanics/molecular mechanics simulations. Cleavage of a fragment of the non-structured protein (NSP) from the SARS-CoV-2 genome was also simulated for reference. Simulations show that both candidates form more stable enzyme-inhibitor (E-I) complexes than the chosen NSP. It was found that both the NSP fragment and the activated ester inhibitor react with CYS145 of M PRO in a concerted manner, whereas the acrylamide inhibitor follows a stepwise mechanism. Most importantly, the reversible reaction and the subsequent hydrolysis reaction from E-I complexes are less probable when compared to the reactions with an NSP fragment, showing promise for these candidates to be the base for efficient M PRO inhibitors.

60 APPLIED LIFE SCIENCES↗

NASA NTRSDate not supplied

TPSAS-NF1676L-30664-DND

- NASA Office of Safety and Mission Assurance (OSMA) Efforts - NASA Material Genome Initiative (MGI) - Following up effort: NASA Additive Manufacturing Structural Integrity Initiative (AMSII) - In-Situ Techniques for Additive Manufacturing

Joseph N. Zalameda↗

DOE OSTI2023

PYK-SubstitutionOME: an integrated database containing allosteric coupling, ligand affinity and mutational, structural, pathological, bioinformatic and computational information about pyruvate kinase isozymes

Interpreting changes in patient genomes, understanding how viruses evolve and engineering novel protein function all depend on accurately predicting the functional outcomes that arise from amino acid substitutions. To that end, the development of first-generation prediction algorithms was guided by historic experimental datasets. However, these datasets were heavily biased toward substitutions at positions that have not changed much throughout evolution (i.e. conserved). Although newer datasets include substitutions at positions that span a range of evolutionary conservation scores, these data are largely derived from assays that agglomerate multiple aspects of function. To facilitate predictions from the foundational chemical properties of proteins, large substitution databases with biochemical characterizations of function are needed. We report here a database derived from mutational, biochemical, bioinformatic, structural, pathological and computational studies of a highly studied protein family—pyruvate kinase (PYK). A centerpiece of this database is the biochemical characterization—including quantitative evaluation of allosteric regulation—of the changes that accompany substitutions at positions that sample the full conservation range observed in the PYK family. We have used these data to facilitate critical advances in the foundational studies of allosteric regulation and protein evolution and as rigorous benchmarks for testing protein predictions. We trust that the collected dataset will be useful for the broader scientific community in the further development of prediction algorithms.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

Structure and function of bacteriophage CBA120 ORF211 (TSP2), the determinant of phage specificity towards E. coli O157:H7

The genome of Escherichia coli O157:H7 bacteriophage vB_EcoM_CBA120 encodes four distinct tailspike proteins (TSPs). The four TSPs, TSP1-4, attach to the phage baseplate forming a branched structure. We report the 1.9 Å resolution crystal structure of TSP2 (ORF211), the TSP that confers phage specificity towards E. coli O157:H7. The structure shows that the N-terminal 168 residues involved in TSPs complex assembly are disordered in the absence of partner proteins. The ensuing head domain contains only the first of two fold modules seen in other phage vB_EcoM_CBA120 TSPs. The catalytic site resides in a cleft at the interface between adjacent trimer subunits, where Asp506, Glu568, and Asp571 are located in close proximity. Replacement of Asp506 and Asp571 for alanine residues abolishes enzyme activity, thus identifying the acid/base catalytic machinery. However, activity remains intact when Asp506 and Asp571 are mutated into asparagine residues. Analysis of additional site-directed mutants in the background of the D506N:D571N mutant suggests engagement of an alternative catalytic apparatus comprising Glu568 and Tyr623. Finally, we demonstrate the catalytic role of two interacting glutamate residues of TSP1, located in a cleft between two trimer subunits, Glu456 and Glu483, underscoring the diversity of the catalytic apparatus employed by phage vB_EcoM_CBA120 TSPs.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Cave Thiovulum ( Candidatus Thiovulum stygium) differs metabolically and genomically from marine species

Thiovulum spp. (Campylobacterota) are large sulfur bacteria that form veil-like structures in aquatic environments. The sulfidic Movile Cave (Romania), sealed from the atmosphere for ~5 million years, has several aqueous chambers, some with low atmospheric O 2 (~7%). The cave’s surface-water microbial community is dominated by bacteria we identified as Thiovulum. We show that this strain, and others from subsurface environments, are phylogenetically distinct from marine Thiovulum. We assembled a closed genome of the Movile strain and confirmed its metabolism using RNAseq. We compared the genome of this strain and one we assembled from public data from the sulfidic Frasassi caves to four marine genomes, including Candidatus Thiovulum karukerense and Ca. T. imperiosus, whose genomes we sequenced. Despite great spatial and temporal separation, the genomes of the Movile and Frasassi Thiovulum were highly similar, differing greatly from the very diverse marine strains. We concluded that cave Thiovulum represent a new species, named here Candidatus Thiovulum stygium. Based on their genomes, cave Thiovulum can switch between aerobic and anaerobic sulfide oxidation using O 2 and NO 3 - as electron acceptors, the latter likely via dissimilatory nitrate reduction to ammonia. Thus, Thiovulum is likely important to both S and N cycles in sulfidic caves. Electron microscopy analysis suggests that at least some of the short peritrichous structures typical of Thiovulum are type IV pili, for which genes were found in all strains. These pili may play a role in veil formation, by connecting adjacent cells, and in the motility of these exceptionally fast swimmers.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2025

Structural insights into transcriptional regulation by the helicase RECQL5

Abstract Transcription poses a major challenge for genome stability. The RECQL5 helicase helps safeguard genome integrity and is the only member of the human RecQ helicase family that directly binds to RNA polymerase II (Pol II) and affects its progression. While RECQL5 mitigates transcription stress in cells, the molecular mechanism underlying this phenomenon is unclear. Here, we use cryo-electron microscopy to determine the structures of stalled human Pol II elongation complexes (ECs) bound to RECQL5. Our structures reveal the molecular interactions stabilizing RECQL5 binding to the Pol II EC and highlight its role as a transcriptional roadblock. Additionally, we find that, in its nucleotide-free state, RECQL5 twists the downstream DNA in the EC and, upon nucleotide binding, undergoes a conformational change that allosterically induces Pol II toward a post-translocation state. We propose that this mechanism may help restart Pol II elongation and, therefore, contribute to reducing transcription stress.

Biochemistry & Molecular Biology↗

DOE OSTI2024

Probing interspecies metabolic interactions within a synthetic binary microbiome using genome-scale modeling

Metabolic interactions within a microbial community play a key role in determining the structure, function, and composition of the community. However, due to the complexity and intractability of natural microbiomes, limited knowledge is available on interspecies interactions within a community. In this work, using a binary synthetic microbiome, a methanotroph-photoautotroph (M-P) coculture, as the model system, we examined different genome-scale metabolic modeling (GEM) approaches to gain a better understanding of the metabolic interactions within the coculture, how they contribute to the enhanced growth observed in the coculture, and how they evolve over time. Using batch growth data of the model M-P coculture, we compared three GEM approaches for microbial communities. Two of the methods are existing approaches: SteadyCom, a steady state GEM, and dynamic flux balance analysis (DFBA) Lab, a dynamic GEM. We also proposed an improved dynamic GEM approach, DynamiCom, for the M-P coculture. SteadyCom can predict the metabolic interactions within the coculture but not their dynamic evolutions; DFBA Lab can predict the dynamics of the coculture but cannot identify interspecies interactions. DynamiCom was able to identify the cross-fed metabolite within the coculture, as well as predict the evolution of the interspecies interactions over time. A new dynamic GEM approach, DynamiCom, was developed for a model M-P coculture. Constrained by the predictions from a validated kinetic model, DynamiCom consistently predicted the top metabolites being exchanged in the M-P coculture, as well as the establishment of the mutualistic N-exchange between the methanotroph and cyanobacteria. The interspecies interactions and their dynamic evolution predicted by DynamiCom are supported by ample evidence in the literature on methanotroph, cyanobacteria, and other cyanobacteria-heterotroph cocultures.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRS2007

High-LET Patterns of DSBs in DNA Loops, the HPRT Gene and Phosphorylation Foci

We present new results obtained with our model based on the track structure and chromatin geometry that predicts the DSB spatial and genomic distributions in a cell nucleus with the full genome represented. The model generates stochastic patterns of DSBs in the physical space of the nucleus filled with the realistic configuration of human chromosomes. The model was re-used to find the distribution of DSBs in a physical volume corresponding to a visible phosphorylation focus believed to be associated with a DSB. The data shows whether there must more than one DSB per foci due to finite size of the visible focus, even if a single DSB is radiochemically responsible for the phosphorylation of DNA in its vicinity. The same model can predict patterns of closely located DSBs in a given gene, or in a DNA loop, one of the large-scale chromatin structures. We demonstrated for the example of the HPRT gene, how different sorts of radiation lead to proximity effect in DSB locations, which is important for modeling gene deletions. The spectrum of intron deletions and total gene deletions was simulated for the HPRT gene. The same proximity effect of DSBs in a loop can hinder DSB restitutions, as parts of the loop between DSBs is deleted with a higher likelihood. The distributions of DSBs and deletions of DNA in a loop are presented.

Ponomarev, Artem L.↗

DOE OSTI2021

Discovery of an Antarctic Ascidian-Associated Uncultivated Verrucomicrobia with Antimelanoma Palmerolide Biosynthetic Potential

The Antarctic marine ecosystem harbors a wealth of biological and chemical innovation that has risen in concert over millennia since the isolation of the continent and formation of the Antarctic circumpolar current. Scientific inquiry into the novelty of marine natural products produced by Antarctic benthic invertebrates led to the discovery of a bioactive macrolide, palmerolide A, that has specific activity against melanoma and holds considerable promise as an anticancer therapeutic. While this compound was isolated from the Antarctic ascidian Synoicum adareanum, its biosynthesis has since been hypothesized to be microbially mediated, given structural similarities to microbially produced hybrid nonribosomal peptide-polyketide macrolides. Here, we describe a metagenome-enabled investigation aimed at identifying the biosynthetic gene cluster (BGC) and palmerolide A-producing organism. A 74-kbp candidate BGC encoding the multimodular enzymatic machinery (hybrid type I-trans-AT polyketide synthase-nonribosomal peptide synthetase and tailoring functional domains) was identified and found to harbor key features predicted as necessary for palmerolide A biosynthesis. Surveys of ascidian microbiome samples targeting the candidate BGC revealed a high correlation between palmerolide gene targets and a single 16S rRNA gene variant (R = 0.83 to 0.99). Through repeated rounds of metagenome sequencing followed by binning contigs into metagenome-assembled genomes, we were able to retrieve a nearly complete genome (10 contigs) of the BGC-producing organism, a novel verrucomicrobium within the Opitutaceae family that we propose here as “Candidatus Synoicihabitans palmerolidicus.” The refined genome assembly harbors five highly similar BGC copies, along with structural and functional features that shed light on the host-associated nature of this unique bacterium.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

Structures of flavivirus RNA promoters suggest two binding modes with NS5 polymerase

Flaviviruses use a ~70 nucleotide stem-loop structure called stem-loop A (SLA) at the 5' end of the RNA genome as a promoter for RNA synthesis. Flaviviral polymerase NS5 specifically recognizes SLA to initiate RNA synthesis and methylate the 5' guanosine cap. We report the crystal structures of dengue (DENV) and Zika virus (ZIKV) SLAs. DENV and ZIKV SLAs differ in the relative orientations of their top stem-loop helices to bottom stems, but both form an intermolecular three-way junction with a neighboring SLA molecule. To understand how NS5 engages SLA, we determined the SLA-binding site on NS5 and modeled the NS5-SLA complex of DENV and ZIKV. Our results show that the gross conformational differences seen in DENV and ZIKV SLAs can be compensated by the differences in the domain arrangements in DENV and ZIKV NS5s. We describe two binding modes of SLA and NS5 and propose an SLA-mediated RNA synthesis mechanism.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRS2017

Exploring Connectivity in Sequence Space of Functional RNA

Emergence of replicable genetic molecules was one of the marking points in the origin of life, evolution of which can be conceptualized as a walk through the space of all possible sequences. A theoretical concept of fitness landscape helps to understand evolutionary processes through assigning a value of fitness to each genotype. Then, evolution of a phenotype is viewed as a series of consecutive, single-point mutations. Natural selection biases evolution toward peaks of high fitness and away from valleys of low fitness. whereas neutral drift occurs in the sequence space without direction as mutations are introduced at random. Large networks of neutral or near-neutral mutations on a fitness landscape, especially for sufficiently long genomes, are possible or even inevitable. Their detection in experiments, however, has been elusive. Although a few near-neutral evolutionary pathways have been found, recent experimental evidence indicates landscapes consist of largely isolated islands. The generality of these results, however, is not clear, as the genome length or the fraction of functional molecules in the genotypic space might have been insufficient for the emergence of large, neutral networks. Thorough investigation on the structure of the fitness landscape is essential to understand the mechanisms of evolution of early genomes. RNA molecules are commonly assumed to play the pivotal role in the origin of genetic systems. They are widely believed to be early, if not the earliest, genetic and catalytic molecules, with abundant biochemical activities as aptamers and ribozymes, i.e. RNA molecules capable, respectively, to bind small molecules or catalyze chemical reactions. Here, we present results of our recent studies on the structure of the sequence space of RNA ligase ribozymes selected through in vitro evolution. Several hundred thousands of sequences active to a different degree were obtained by way of deep sequencing. Analysis of these sequences revealed several large clusters defined such that every sequence in a cluster can be reached from any other sequence in the same cluster through a series of single point mutations. Sequences in a single cluster appear to adopt more than one secondary structure. The mechanism of refolding within a single cluster was examined. To shed light on possible evolutionary paths in the space of ribozymes, the connectivity between clusters was investigated. The effect of length of RNA molecules on the structure of the fitness landscape and possible evolutionary paths was examined by way of comparing functional sequences of 20 and 80 nucleobases in length. It was found that sequences of different lengths shared secondary structure motifs that were presumed responsible for catalytic activity, with increasing complexity and global structural rearrangements emerging in longer molecules.

Wei, Chenyu↗

DOE OSTI2026

Comparative genomics provides insights into the cold adaptation of endophytic fungi associated with Deschampsia antarctica

Endophytic fungi from Deschampsia antarctica , the southernmost flowering plant, provide insights into the cold adaptation mechanisms of plant-associated fungi in extreme environments. This study presents the genome sequences and comparative analysis of eight fungal isolates from D. antarctica leaves. These Antarctic fungal isolates were analyzed alongside 121 plant-associated fungal genomes to uncover signatures of adaptation and endophytic specialization. Antarctic endophytes show striking patterns, including reduced genome size (∼26.3 Mb on average), streamlined gene content (∼8844 genes), and notably small secretomes (∼288 proteins). Despite this reduced gene repertoire, they maintain a robust set of genes encoding carbohydrate-active enzymes (CAZymes) but lack those for lignin and bacterial cell wall degradation, indicating a symbiotic lifestyle that avoids host damage and predation. One isolate, Alternaria sp. UNIPAMPA017 stood out, with 26% of its genome occupied by transposable elements. Lifestyle, rather than phylogeny, was the main driver of CAZyme and secretome profiles, underscoring ecological convergence. Compared to endophytes from Arabidopsis and Populus, D. antarctica endophytes harbor fewer pectin-degrading enzymes, reflecting their adaptation to the cell wall structure of their monocot host. Together, these fungi reveal a pattern of genomic reduction and functional fine-tuning, hallmarks of life adapted to persist in cold, nutrient-scarce niches.

Ascomycota↗

DOE OSTI2021

Mitochondrial Genomes of the United States Distribution of Gray Fox (Urocyon cinereoargenteus) Reveal a Major Phylogeographic Break at the Great Plains Suture Zone

We examined phylogeographic structure in gray fox (Urocyon cinereoargenteus) across the United States to identify the location of secondary contact zone(s) between eastern and western lineages and investigate the possibility of additional cryptic intraspecific divergences. We generated and analyzed complete mitochondrial genome sequence data from 75 samples and partial control region mitochondrial DNA sequences from 378 samples to investigate levels of genetic diversity and structure through population- and individual-based analyses including estimates of divergence (FST and SAMOVA), median joining networks, and phylogenies. We used complete mitochondrial genomes to infer phylogenetic relationships and date divergence times of major lineages of Urocyon in the United States. Despite broad-scale sampling, we did not recover additional major lineages of Urocyon within the United States, but identified a deep east-west split (~0.8 million years) with secondary contact at the Great Plains Suture Zone and confirmed the Channel Island fox (Urocyon littoralis) is nested within U. cinereoargenteus. Genetic diversity declined at northern latitudes in the eastern United States, a pattern concordant with post-glacial recolonization and range expansion. Beyond the east-west divergence, morphologically-based subspecies did not form monophyletic groups, though unique haplotypes were often geographically limited. Gray foxes in the United States displayed a deep, cryptic divergence suggesting taxonomic revision is needed. Secondary contact at a common phylogeographic break, the Great Plains Suture Zone, where environmental variables show a sharp cline, suggests ongoing evolutionary processes may reinforce this divergence. Follow-up study with nuclear markers should investigate whether hybridization is occurring along the suture zone and characterize contemporary population structure to help identify conservation units. Comparative work on other wide-ranging carnivores in the region should test whether similar evolutionary patterns and processes are occurring.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2020

Different tertiary interactions create the same important 3D features in a distinct flavivirus xrRNA

During infection by a flavivirus (FV), cells accumulate noncoding subgenomic flavivirus RNAs (sfRNAs) that interfere with several antiviral pathways. These sfRNAs are formed by structured RNA elements in the 3' untranslated region (UTR) of the viral genomic RNA, which block the progression of host cell exoribonucleases that have targeted the viral RNA. Previous work on these exoribonuclease-resistant RNAs (xrRNAs) from mosquito-borne FVs revealed a specific three-dimensional fold with a unique topology in which a ring-like structure protectively encircles the 5' end of the xrRNA. Conserved nucleotides make specific tertiary interactions that support this fold. Examination of more divergent FVs reveals differences in their 3' UTR sequences, raising the question of whether they contain xrRNAs and if so, how they fold. To answer this, we demonstrated the presence of an authentic xrRNA in the 3' UTR of the Tamana bat virus (TABV) and solved its structure by X-ray crystallography. The structure reveals conserved features from previously characterized xrRNAs, but in the TABV version these features are created through a novel set of tertiary interactions not previously seen in xrRNAs. This includes two important A–C interactions, four distinct backbone kinks, several ordered Mg 2+ ions, and a C + –G–C base triple. The discovery that the same overall architecture can be achieved by very different sequences and interactions in distantly related flaviviruses provides insight into the diversity of this type of RNA and will inform searches for undiscovered xrRNAs in viruses and beyond.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Primer terminal ribonucleotide alters the active site dynamics of DNA polymerase η and reduces DNA synthesis fidelity

DNA polymerases catalyze DNA synthesis with high efficiency, which is essential for all life. Extensive kinetic and structural efforts have been executed in exploring mechanisms of DNA polymerases, surrounding their kinetic pathway, catalytic mechanisms, and factors that dictate polymerase fidelity. Recent time-resolved crystallography studies on DNA polymerase η (Pol η) and β have revealed essential transient events during the DNA synthesis reaction, such as mechanisms of primer deprotonation, separated roles of the three metal ions, and conformational changes that disfavor incorporation of the incorrect substrate. DNA-embedded ribonucleotides (rNs) are the most common lesion on DNA and a major threat to genome integrity. While kinetics of rN incorporation has been explored and structural studies have revealed that DNA polymerases have a steric gate that destabilizes ribonucleotide triphosphate binding, the mechanism of extension upon rN addition remains poorly characterized. Using steady-state kinetics, static and time-resolved X-ray crystallography with Pol η as a model system, we showed that the extra hydroxyl group on the primer terminus does alter the dynamics of the polymerase active site as well as the catalysis and fidelity of DNA synthesis. During rN extension, Pol η error incorporation efficiency increases significantly across different sequence contexts. Finally, our systematic structural studies suggest that the rN at the primer end improves primer alignment and reduces barriers in C2'-endo to C3'-endo sugar conformational change. Overall, our work provides further mechanistic insights into the effects of rN incorporation on DNA synthesis.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRS2020

Prochlorococcus phage ferredoxin: structural characterization and electron transfer to cyanobacterial sulfite reductases

Marine cyanobacteria are infected by phages whose genomes encode ferredoxin (Fd) electron carriers. These Fds are thought to redirect the energy harvested from light to phage-encoded oxidoreductases that enhance viral fitness, but it is unclear how the biophysical properties and partner specificities of phage Fds relate to those of photosynthetic organisms. Here, results of a bioinformatics analysis using a sequence similarity network revealed that phage Fds are most closely related to cyanobacterial Fds that transfer electrons from photosystems to oxidoreductases involved in nutrient assimilation. Structural analysis of myovirus P-SSM2 Fd (pssm2-Fd), which infects the cyanobacterium Prochlorococcus marinus, revealed high levels of similarity to cyanobacterial Fds (root mean square deviations of ≤0.5 Å). Additionally, pssm2-Fd exhibited a low midpoint reduction potential (–336 mV versus a standard hydrogen electrode), similar to other photosynthetic Fds, although it had lower thermostability (Tm = 28 °C) than did many other Fds. When expressed in an Escherichia coli strain deficient in sulfite assimilation, pssm2-Fd complemented bacterial growth when coexpressed with a P. marinus sulfite reductase, revealing that pssm2-Fd can transfer electrons to a host protein involved in nutrient assimilation. The high levels of structural similarity with cyanobacterial Fds and reactivity with a host sulfite reductase suggest that phage Fds evolved to transfer electrons to cyanobacterially encoded oxidoreductases.

cyanobacteria↗