Lars Barquist

All-at-once RNA folding with 3D motif prediction framed by evolutionary information - Nature Methods Structural RNAs exhibit a vast array of recurrent short three-dimensional (3D) elements found in loop regions involving non-Watson–Crick interactions that help arrange canonical double helices into tertiary structures. Here we present CaCoFold-R3D, a probabilistic grammar that predicts these RNA 3D motifs (also termed modules) jointly with RNA secondary structure over a sequence or alignment. CaCoFold-R3D uses evolutionary information present in an RNA alignment to reliably identify canonical helices (including pseudoknots) by covariation. Here we further introduce the R3D grammars, which also exploit helix covariation that constrains the positioning of the mostly noncovarying RNA 3D motifs. Our method runs predictions over an almost-exhaustive list of over 50 known RNA motifs (‘everything’). Motifs can appear in any nonhelical loop region (including three-way, four-way and higher junctions) (‘everywhere’). All structural motifs as well as the canonical helices are arranged into one single structure predicted by one single joint probabilistic grammar (‘all-at-once’). Our results demonstrate that CaCoFold-R3D is a valid alternative for predicting the all-residue interactions present in a RNA 3D structure. CaCoFold-R3D is fast and easily customizable for novel motif discovery and shows promising value both as a strong input for deep learning approaches to all-atom structure prediction as well as toward guiding RNA design as drug targets for therapeutic small molecules.

Integrated prediction of RNA secondary structure jointly with 3D motifs and pseudoknots guided by evolutionary information.
@aakaran31.bsky.social and @rivaselenarivas.bsky.social

link.springer.com/article/10.1...

🚨PHD PROJECT!🚨
Interested in #bacteria, #RNA, #evolution, #biotech, #EnvironmentalMicro?

Opportunity for a fully-funded #PhD with me, @rachelmwheatley.bsky.social, & @walllabuoglasgow.bsky.social via the NorthWestBio DTP:

www.gla.ac.uk/postgraduate...

Deadline 21 Nov. #MicroSky Please share!

Apply for a #PhD with @paulhoskisson.bsky.social and me on all things #Streptomyces, #evolution, #AMR, #antibiotics, #biotech!

Deadline 21st November. #MicroSky please share!

#microsky

Courses

On Wed, Dec 10 I will be offering my comprehensive introduction to regression modeling at a steep discount in an effort to raise funds for World Central Kitchen and United Farm Workers. Details about the course and registration process can be found on my website, betanalpha.github.io/courses/.

Come and work with me and @ariannebabina.bsky.social on #Streptomyces evolution and antibiotic production

Origins of a tangled bank: Adaptation and evolution in antibiotic-producing Streptomyces

www.gla.ac.uk/postgraduate...

please repost

Excited to share this cool cold shock 😅 work of Yan Zhang ! scholar.google.com/citations?us...

#microsky

Uncertainty Modeling Outperforms Machine Learning for Microbiome Data Analysis Microbiome sequencing measures relative rather than absolute abundances, providing no direct information about total microbial load. Normalization methods attempt to compensate, but rely on strong, of...

New Paper!

Machine learning models that attempt to predict microbial load collapse outside of their training context with an R2<0!

In contrast, our Bayesian Partially Identified Models embrace uncertainty in unmeasured microbial load and consistently outpreform.

www.biorxiv.org/content/10.1...

And importantly Hainan to complete the chicken rice archipelago.

Population densities and frequencies of protease-deficient mutants over time. Differences in environmental factors associated with inflammation varied the population density (A) and the frequency of evolved protease-deficient mutants, PDMs (B), over time. Box plot tracks the average and overall distribution of population density at each detected time point within each selective environment. Each line shows the tracked population density or PDM frequency along the daily passage in a single population, grouped by selective environments (Casein SCFM or casamino acids, labeled CAA SCFM, and with or without supplemented 2 mM hydrogen peroxide, OS±).

Using experimental evolution in host-mimicking media, researchers show that inflammation-like environments limit the loss of quorum sensing—a common adaptation during chronic infections—in Pseudomonas aeruginosa. Learn more in #mSystems: asm.social/2vd

Hydrogen sulfide production distinguishes Salmonella from close relatives, but its biological significance remains obscure. This study uncovers the secret: Salmonella uses hydrogen sulfide production as a weapon to outcompete E. coli and gain a foothold in the gut.
www.pnas.org/doi/10.1073/...

Revealing Community Dynamics in Polymicrobial Infections through a Quantitative Framework Laboratory models provide tractable, reproducible systems that have long served as foundational tools in microbiology. However, the extent to which these models accurately mimic the biological environ...

Excited to share our latest preprint is up: www.biorxiv.org/content/10.1... led by @aanuoluwaduro.bsky.social ! 🧪🧫

Translational coupling of neighboring genes in prokaryotes | Journal of Bacteriology Prokaryotic genes are arranged in operons, with functionally related genes often located adjacent to one another (1). There are several ways in which the operonic organization of genes facilitates the...

Check out our new paper: a review of translational coupling, the phenomenon where translation of one prokaryotic gene can promote translation of the gene downstream. We cover the history, and delve into the mechanism, which is still not fully understood. journals.asm.org/doi/10.1128/...

Programmable antisense oligomers for phage functional genomics - Nature Establishing antisense oligomers as versatile, non-genetic tools to silence phage mRNAs opens applications in basic research and biotechnology, as shown by identifying essential factors for propagatio...

No Genetics? Try ASOs – A non-genetic approach to silence genes at the phage-host interface. We use it to study jumbo phage biology and anti-phage defence.
@jorg-vogel-lab.bsky.social @helmholtz-hiri.bsky.social
@uni-wuerzburg.de @helmholtzhzi.bsky.social
published now in @nature.com

Looking for a new approach to studying or eliminating phages? Check out our study introducing anti-phage ASOs (antisense oligos) out in @Nature today. nature.com/articles/s4158…

Phages, viruses that infect bacteria, could help fight antibiotic resistance, but phage–host interactions are not yet sufficiently understood. Researchers from #HIRI, JMU & HZI now successfully interfered with phage reproduction using ASOs.
Just out in @nature.com:
www.nature.com/articles/s41...

MLCB - Schedule The in-person component will be held at the New York Genome Center, 101 6th Ave, New York, NY 10013. All times below are Eastern Time.

2025 Machine Learning in Computational Biology (#MLCB) meeting starts TODAY (9/10) at 9:30a (EST) at the NY Genome Center in NYC!

We have a great lineup of keynotes, contributed talks, and posters today and tomorrow

Schedule: mlcb.org/schedule

Join for free via livestream: m.youtube.com/@mlcbconf

Efficient sequence alignment against millions of prokaryotic genomes with LexicMap - Nature Biotechnology LexicMap uses a fixed set of probes to efficiently query gene sequences for fast and low-memory alignment.

Sometimes you meet absolutely incredible bioinfo-magicians.
It was a huge privilege when @shenwei356.bsky.social
joined our group for a year on an @embl.org sabbatical.
While here, he developed a new way of aligning to
millions of bacteria, called LexicMap 1/n
www.nature.com/articles/s41...

An RNA regulates iron homeostasis and host mucus colonization in Bacteroides thetaiotaomicron Symbiotic bacteria in the human intestinal microbiota provide many pivotal functions to human health and occupy distinct biogeographic niches within the gut. Yet the molecular basis underlying niche-s...

New preprint from the lab, in collaboration with Wenhan Zhu (U Vanderbilt): using dual RNA-seq during B. theta colonization of the host mucous layer, we identify IroR--an iron-response sRNA that tunes capsule expression and facilitates adaptation to iron limitation.
doi.org/10.1101/2025.09.08.672848

RNAcanvas: interactive drawing and exploration of nucleic acid structures Abstract. Two-dimensional drawing of nucleic acid structures, particularly RNA structures, is fundamental to the communication of nucleic acids research. H

🧪 #RNAsky

If you aren’t using RNAcanvas to draw your RNA structures and explore alternative structures, you are missing out! 56 citations in a year, with multiple ones in top journals like Nature, Science & Cell. Easy to use and packed with unique features! Try it!

academic.oup.com/nar/article/...

Genomic constraints shape the evolution of alternative routes to drug resistance in prokaryotes Background Variation within the prokaryotic pangenome is not random, and natural selection that favours particular combinations of genes appears to dominate over random drift. What is less clear is wh...

New preprint reveals bacteria can't just collect all resistance genes like Pokemon cards.
We found mutually exclusive evolutionary pathways to multidrug resistance in E. coli & P. aeruginosa - some resistance mechanisms actively prevent others from coexisting www.biorxiv.org/content/10.1...

The 2024 rankings of bacterial threats

tangermeme: A toolkit for understanding cis-regulatory logic using deep learning models Deep learning models have achieved state-of-the-art performance at predicting diverse genomic modalities, yet their promise for biological discovery lies in how they are used after demonstrating their...

Preprint: biorxiv.org/content/10.1...

Installation: `pip install tangermeme`

Frequency-dependent fitness effects are ubiquitous In simple microbial populations, the fitness effects of most selected mutations are generally taken to be constant, independent of genotype frequency. This assumption underpins predictions about evolutionary dynamics, epistatic interactions, and the maintenance of genetic diversity in populations. Here, we systematically test this assumption using beneficial mutations from early generations of the Escherichia coli Long-Term Evolution Experiment (LTEE). Using flow cytometry-based competition assays, we find that frequency-dependent fitness effects are the norm rather than the exception, occurring in approximately 80\% of strain pairs tested. Most competitions exhibit negative frequency-dependence, where fitness advantages decline as mutant frequency increases. Furthermore, we demonstrate that the strength of frequency-dependence is predictable from invasion fitness measurements, with invasion fitness explaining approximately half of the biological variation in frequency-dependent slopes. Additionally, we observe violations of fitness transitivity in several strain combinations, indicating that competitive relationships cannot always be predicted from fitness relative to a single reference strain alone. Through high-resolution measurements of within-growth cycle dynamics, we show that simple resource competition explains a substantial portion of the frequency-dependence: when faster-growing genotypes dominate populations, they deplete shared resources more rapidly, reducing the time available for fitness differences to accumulate. Our results demonstrate that even in a simple model system designed to minimize ecological complexity, subtle ecological interactions between closely related genotypes create frequency-dependent selection that can fundamentally alter evolutionary dynamics. ### Competing Interest Statement The authors have declared no competing interest.

How common are frequency dependent fitness effects?

New preprint out today 👇
doi.org/10.1101/2025...

I haven’t had the chance to look closely, but I’m still eager to share this practical guide on Simulation-based Inference 👇

Conservation and evolution of the programmed ribosomal frameshift in prfB across the bacterial domain | mBio Translation termination is catalyzed by one of two release factors in bacteria, RF1 or RF2. It has been known for decades that RF2 levels in Escherichia coli are regulated by a programmed ribosomal frameshift within the prfB gene that encodes RF2. We ...

Latest from the lab! Analysis of everyone’s favorite regulatory mechanism in bacteria — the RF2 programmed frameshift! Likely present in the ancestor of bacteria, use of this mechanism is influenced by stop codon usage! Big congrats to @cassidyprints.bsky.social
journals.asm.org/doi/10.1128/...

That's the new MDPI journal on septicemic enteropathogens.

Cholera toxin-induced disease generates epithelial cell-derived L-lactate that promotes Vibrio cholerae growth in the small intestine Cholera toxin (CT) promotes Vibrio cholerae colonization by altering gut metabolism to favor pathogen growth. We have previously found that CT-induced disease leads to increased concentrations of L-la...

1/ Excited to share the first preprint from my lab! 🎉

My postdoc Paz asked how cholera toxin (CT) helps Vibrio cholerae thrive in the gut.

Turns out, CT rewires epithelial metabolism toward L-lactate production—fueling pathogen growth in the small intestine during disease

Mathematical modelling for biologists - Modelling concepts in biological research Mathematical modelling for biologists - Modelling concepts in biological research

My PhD student @leonielorenz.bsky.social (with Eva Geissen) has made this nice (free) online course to introduce mathematical modelling for biology:
www.ebi.ac.uk/training/onl...

Including both molecular and epidemiological examples